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US20210154213A1 - Pharmacological agents for treating ocular diseases - Google Patents

Pharmacological agents for treating ocular diseases Download PDF

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Publication number
US20210154213A1
US20210154213A1 US17/045,430 US201917045430A US2021154213A1 US 20210154213 A1 US20210154213 A1 US 20210154213A1 US 201917045430 A US201917045430 A US 201917045430A US 2021154213 A1 US2021154213 A1 US 2021154213A1
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alkyl
halo
cycloalkyl
hydrogen
group
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US11872236B2 (en
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Surya Kanta De
Sridhar G. Prasad
Marshall Clarke Peterman
Bernard Collins
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Plex Pharmaceuticals Inc
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Calasia Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • Presbyopia is the loss of accommodative ability of the eye resulting in the inability to focus on near objects. Presbyopia affects everyone over the age of 45 and has significant negative impacts on the quality of life.
  • Current treatments for presbyopia include: (i) non-invasive approaches that utilize devices to help improve near and distance vision but do nothing to restore the natural process of accommodation and require constant use of the devices, and (ii) invasive surgical procedures which are associated with major complications including decrease in vision quality, regression effects, anisometropia, corneal ectasia, and haze. Most importantly, none of these methods can reverse presbyopia. Moreover, no treatment option exists that can either prevent or delay the onset of presbyopia.
  • CM ciliary muscle
  • proteins known as crystallins play a major role in the stiffening of the eye lens.
  • the lens crystallins comprise three isoforms, ⁇ , ⁇ , and ⁇ and make up 90% of the eye lens protein content.
  • ⁇ crystalline (AC) an ATP-independent chaperone and member of the small heat shock protein (sHsp) family, constitutes 40% of the crystallin protein content. It exists as a hetero-oligomer of two subunits, ⁇ A-crystallin (AAC) and ⁇ B-crystallin (ABC) and its expression is primarily restricted to the eye lens. It recognizes exposed conformational features in partially unfolded lens proteins and sequesters them from one another, thereby reducing the population of aggregation-prone species that would otherwise lead to various age-related vision impairment.
  • presbyopia is the earliest observable symptom of age-related nuclear (ARN) cataract, a major cause of blindness in the world.
  • ARN age-related nuclear
  • SMDs small molecule disaggregases
  • hAAC HMW aggregates human ACC
  • a method for treating presbyopia or cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (VII)
  • R 1 is independently selected from the group consisting of hydrogen; (C 1 -C 3 )alkyl; halo(C 1 -C 3 )alkyl; (C 3 -C 6 )cycloalkyl; halo(C 3 -C 6 )cycloalkyl; (C 1 -C 3 )alkyloxy; and R 4 C ⁇ O; wherein R 4 is selected from the (C 1 -C 6 )alkyl; halo(C 1 -C 6 )alkyl; (C 3 -C 6 )cycloalkyl; halo(C 3 -C 6 )cycloalkyl; aryl; haloaryl; and
  • R 7 is (C 1 -C 6 )alkyl and R 8 is (C 1 -C 6 )alkyl, aryl, or a polyethylene glycol group;
  • R 2 is independently selected from the group consisting of hydrogen, R 5 , OR 5 , N(R 5 )(R 6 ), halide, CN, NO 2 , C(O)OR 5 , CON(R 5 )(R 6 ), S(O)NR 5 2 , SO 3 H, SO 2 CH 3 , phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R 5 and R 6 are independently selected from hydrogen atom, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, and (C 3 -C 6 )cycloal
  • R 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, and hydroxy(C 2 -C 6 )alkenyl.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 1 is selected from the group consisting of
  • R 7 is (C 1 -C 6 )alkyl and R 8 is (C 1 -C 6 )alkyl, aryl, or a polyethylene glycol group.
  • each R 1 is a hydrogen atom. In another embodiment, each R 1 is an alkyl. In yet another embodiment, one R 1 is a hydrogen or an alkyl, and the other R 1 is a carboxyl, benzoxyl, or a methoxyl. In one embodiment, the compound is
  • a method for treating presbyopia or cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (I)
  • R 1 is R 8 or R 8 C ⁇ O, wherein R 8 is selected from hydrogen, (C 1 -C 6 )alkyl and (C 3 -C 6 )cycloalkyl groups, wherein the alkyl and the cycloalkyl groups are optionally substituted with one or more fluorine atoms;
  • R 2 is aryl, (C 1 -C 3 )alkylaryl, heteroaryl, (C 1 -C 3 )alkylheteroarylalkyl, (C 1 -C 3 )alkylheterocyclyl, each of which is optionally substituted with up to 3 groups independently selected from R 11 ;
  • R 3 , R 4 , R 5 , R 6 , and R 7 are independently selected from hydrogen, R 9 , OR 9 , N(R 9 )(R 10 ), halogen, CN, NO 2 , C(O)OR 9 , CON(R 9 )(R 10 ), S(O)NR 9 2 , SO 3 H, SO 2 CH 3 , phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R 9 and R 10 are independently selected from hydrogen atom, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl,
  • R 11 is selected from the group consisting of oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C 1 -C 6 )alkylheteroaryl, halo(C 1 -C 6 )alkylheteroaryl, hydroxy(C 1 -C 6 )alkylheteroaryl, (C 3 -C 6 )cycloalkylheteroaryl, halo(C 3 -C 6 )cycloalkylheteroaryl, hydroxy(C
  • R 7 is hydrogen.
  • R 6 is hydrogen.
  • R 3 is hydrogen.
  • R 5 is hydrogen. In one embodiment, R 4 is hydrogen.
  • R 2 is a heteroaryl having one ring nitrogen. In one embodiment, R 2 is a heteroaryl having two ring nitrogen atoms. In one embodiment, R 2 is a heteroaryl having one or two ring nitrogen, the ring optionally substituted with up to two (C 1 -C 6 )alkyl groups. In one embodiment, R 2 is a heteroaryl having one or two ring nitrogen, the ring optionally substituted with up to two (C 1 -C 6 )alkyl groups and an oxo group. In one embodiment, the compound is one of
  • a method for treating presbyopia or cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (II)
  • X is CH 2 or C ⁇ O
  • n 1 or 2
  • R 1 , R 4 , and R 5 are independently selected from hydrogen, R 6 , OR 6 , N(R 6 )(R 7 ), halide, CN, NO 2 , C(O)OR 6 , CON(R 6 )(R 7 ), S(O)NR 6 2 , SO 3 H, SO 2 CH 3 , phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R 6 and R 7 are independently selected from hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, and (C 3 -C 6 )cycl
  • R 2 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl group;
  • R 3 is aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with up to 3 groups independently selected from R 8 ;
  • R 8 is selected from the group consisting of oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C 1 -C 6 )alkylheteroaryl, halo(C 1 -C 6 )alkylheteroaryl, hydroxy(C 1 -C 6 )alkylheteroaryl, (C 3 -C 6 )cycloalkylheteroaryl, halo(C 3 -C 6 )cycloalkylheteroaryl, hydroxy(C
  • R 1 is a (C 3 -C 6 )cycloalkyl, and substitutes one or two ring hydrogen atoms.
  • R 1 is a cyclopropyl, and substitutes one ring hydrogen atom.
  • R 1 is a (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl.
  • R 1 is cyclopropylmethyl.
  • R 5 is hydrogen.
  • R 5 is hydrogen, and R 1 is a (C 3 -C 6 )cycloalkyl, and substitutes one or two ring hydrogen atoms.
  • R 5 is hydrogen and R 1 is a (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl.
  • X is CH 2 and R 2 is (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl group.
  • R 3 is an aryl. In one embodiment, R 3 is a heteroaryl. In one embodiment, the compound is one of
  • a method for treating presbyopia or cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (III)
  • X is N
  • p is 0 or 1;
  • n 0, 1, or 2;
  • R 1 , R 4 , and R 5 are independently selected from hydrogen R 6 , OR 6 , N(R 6 )(R 7 ), halide, CN, NO 2 , C(O)OR 6 , CON(R 6 )(R 7 ), S(O)NR 6 2 , SO 3 H, SO 2 CH 3 , phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R 6 and R 7 are independently selected from hydrogen atom, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, and (C 3 -C 6 )
  • R 2 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, and (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
  • R 3 is one of hydrogen, R 8 and SO 2 R 8 , wherein R 8 is selected from the group consisting of aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with up to 3 groups independently selected from R 9 ;
  • R 9 is selected from the group consisting of oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C 1 -C 6 )alkylheteroaryl, halo(C 1 -C 6 )alkylheteroaryl, hydroxy(C 1 -C 6 )alkylheteroaryl, (C 3 -C 6 )cycloalkylheteroaryl, halo(C 3 -C 6 )cycloalkylheteroaryl, hydroxy(C
  • R 1 is hydrogen. In one embodiment, R 1 is hydrogen and each of p and n is zero. In one embodiment, X is N. In one embodiment, X is N and R 2 is a cyclopropyl. In one embodiment, each of R 1 , R 4 and R 5 are hydrogen. In one embodiment, R 3 is a heteroaryl group. In one embodiment, R 3 is a heteroaryl substituted with a heterocyclyl group. In one embodiment, R 3 is SO 2 R 8 , wherein R 8 is a heteroaryl. In one embodiment, the compound is one of
  • a method for treating presbyopia or cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (IV)
  • R 1 and R 3 are independently hydrogen, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, and halo(C 3 -C 6 )cycloalkyl;
  • R 2 is selected from the group consisting of hydrogen, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, and R 5 C ⁇ O, wherein R 5 is selected from the (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, aryl, and haloaryl;
  • X is O, S, or NH
  • R 4 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, and hydroxy(C 2 -C 6 )alkenyl.
  • X is O. In one embodiment, X is NH. In one embodiment, X is NH and R 4 is (C 2 -C 6 )alkenyl. In one embodiment, R 1 is a methyl. In one embodiment, R 2 is hydrogen. In one embodiment, R 3 is methyl. In one embodiment, the compound is one of
  • a method for treating presbyopia or cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (V)
  • R 1 is independently selected from hydrogen, R 5 , OR 5 , N(R 5 )(R 6 ), halide, CN, NO 2 , C(O)OR 5 , CON(R 5 )(R 6 ), S(O)NR 6 2 , SO 3 H, SO 2 CH 3 , phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R 5 and R 6 are independently selected from hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, and (C 3 -C 6 )cycloalkylhalo(C 1
  • R 2 is aryl, heteroaryl or heterocycyl, each of which is optionally substituted with up to 3 groups independently selected from R 7 ;
  • R 7 is selected from the group consisting of oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, hydroxy(C 3 -C 6 )cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C 1 -C 6 )alkylheteroaryl, halo(C 1 -C 6 )alkylheteroaryl, hydroxy(C 1 -C 6 )alkylheteroaryl, (C 3 -C 6 )cycloalkylheteroaryl, halo(C 3 -C 6 )cycloalkylheteroaryl, hydroxy(C
  • R 3 is selected from the group consisting of hydrogen, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, and R 8 C ⁇ O, wherein R 8 is selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, aryl, and haloaryl groups; and
  • R 4 is selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, and hydroxy(C 2 -C 6 )alkenyl.
  • R 1 is hydrogen.
  • R 2 is aryl.
  • R 2 is heteroaryl.
  • R 4 is (C 1 -C 6 )alkyl.
  • R 3 is hydrogen.
  • the compound is
  • a method for treating presbyopia or cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (VI)
  • X is H or OR 1 ;
  • R 1 is independently selected from the group consisting of hydrogen, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, and R 3 C ⁇ O, wherein R 3 is selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, aryl, and haloaryl groups; and
  • R 2 is independently selected from hydrogen, R 4 , OR 4 , N(R 4 )(R 5 ), halide, CN, NO 2 , C(O)OR 4 , CON(R 4 )(R 4 ), S(O)NR 42 , SO 3 H, SO 2 CH 3 , phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R 4 and R 5 are independently selected from hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, and (C 3 -C 6 )cycloalkylhalo(C 1
  • X in the unfused benzene ring, X is a hydrogen. In one embodiment, in the unfused benzene ring, X is a hydroxyl. In one embodiment, R 1 is hydrogen. In one embodiment, R 2 is hydrogen. In one embodiment, the compound is one of
  • a method for treating presbyopia or cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (VIII)
  • R 1 is selected from hydrogen, halogen, hydroxyl, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, and halo(C 2 -C 6 )alkenyl;
  • R 2 is selected from hydrogen, R 3 , OR 3 , N(R 3 )(R 4 ), halide, CN, NO 2 , C(O)OR 3 , CON(R 3 )(R 4 ), S(O)NR 32 , SO 3 H, SO 2 CH 3 , phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R 3 and R 4 are independently selected from hydrogen atom, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, and (C 3 -C 6 )cycloalkylhalo(C 1
  • n is an integer between 0 and 4.
  • R 1 is a halogen atom.
  • R 1 is a (C 2 -C 6 )alkenyl.
  • R 2 is a halogen atom.
  • each of R 1 and R 2 is a halogen atom.
  • the compound is one of
  • a method for treating presbyopia or cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (IX)
  • R 1 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 2 -C 6 )alkenyl, halo(C 2 -C 6 )alkenyl, and hydroxy(C 2 -C 6 )alkenyl;
  • X is a hydrogen, halogen, hydroxy or, (C 1 -C 6 )alkyl
  • R 2 is selected from hydrogen, R 3 , OR 4 , N(R 3 )(R 4 ), halide, CN, NO 2 , C(O)OR 3 , CON(R 3 )(R 4 ), S(O)NR 3 2 , SO 3 H, SO 2 CH 3 , phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R 3 and R 4 are independently selected from hydrogen atom, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, and (C 3 -C 6 )cycloalkylhalo(C
  • X is a halogen.
  • R 1 is an alkyl.
  • R 2 is hydrogen.
  • the compound is
  • a method for treating presbyopia or cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (X)
  • X is O, S, or N
  • each of n and p is an integer between 1 and 3;
  • R 1 is aryl, heteroaryl, cyclyl, or heterocycyl, each of which is optionally substituted with up to 3 groups independently selected from R 3 ;
  • R 2 is selected from a group consisting of hydrogen R 4 , OR 4 , N(R 4 )(R 5 ), halide, CN, NO 2 , C(O)OR 4 , CON(R 4 )(R 5 ), S(O)NR 42 , SO 3 H, SO 2 CH 3 , phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R 4 and R 5 are independently selected from a group consisting of hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, and (C 3 -C 6 )cycl
  • R 3 is selected from the group consisting of (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, and R 6 C ⁇ O, wherein R 6 is selected from the (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, aryl, and haloaryl.
  • X is an oxygen atom. In one embodiment, X is an oxygen atom and each of n and p is 1. In one embodiment, R 1 is an aryl. In one embodiment, R is hydrogen. In one embodiment, the compound is
  • a method for treating presbyopia or cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (XI)
  • R 1 is selected from the group consisting of hydrogen (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, and R 3 C ⁇ O, wherein R 3 is selected from the (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, aryl, and haloaryl;
  • X is a hydrogen, halogen, hydroxy or, (C 1 -C 6 )alkyl
  • R 2 is selected from the group consisting of hydrogen, R 4 , OR 4 , N(R 4 )(R 5 ), halide, CN, NO 2 , C(O)OR 4 , CON(R 4 )(R 5 ), S(O)NR 42 , SO 3 H, SO 2 CH 3 , phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R 4 and R 5 are independently selected from hydrogen atom, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, halo(C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, and (C 3 -C 6 )cycloalkyl
  • R 1 is a (C 1 -C 3 )alkyl.
  • R 2 is hydrogen.
  • X is a halogen.
  • the compound is
  • a method of treating presbyopia or cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (XVII) or (XVIII)
  • R 2 is H, X—R, CH 3 , lower alkyl, OCH 3 , OH, F, Cl, Br, NR, —CN, CO 2 R, CH 2 OH, or CF 3 .
  • R is OH
  • X is NH, O, S, SO 2 , or N(C 1 -C 6 )alkyl.
  • a method of treating presbyopia or cataract in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula (XII)
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, (C 1 -C 3 )alkyl; halo(C 1 -C 3 )alkyl; (C 3 -C 7 )cycloalkyl; halo(C 3 -C 7 )cycloalkyl; and phenyl(C 1 -C 3 )alkyl, aminopheny(C 1 -C 3 )alkyl, and indanyl, wherein the phenyl or indanyl is optionally substituted with a halogen and the amino is optionally substituted with one or two (C 1 -C 3 )alkyl;
  • R 3 is selected from the group consisting of hydrogen, (C 3 -C 10 )cycloalkyl; halo(C 3 -C 10 )cycloalkyl; (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl; halo(C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl; (C 1 -C 20 )alkyl; halo(C 1 -C 20 )alkyl; aryl; haloaryl; aryl(C 1 -C 6 )alkyl; haloaryl(C 1 -C 6 )alkyl; and (C 3 -C 10 )heterocyclyl and halo(C 3 -C 10 )heterocyclyl, each optionally substituted at the heteroatom with R 7 CO, wherein R 7 is selected from the group consisting of (C 1 -C 6 )alkyl, halo(
  • R 4 at each position where it occurs, is independently selected from the group consisting of hydrogen; halogen; (C 1 -C 3 )alkyl; halo(C 1 -C 3 )alkyl; (C 1 -C 3 )alkoxy; halo(C 1 -C 3 )alkoxy; OH, thiol, amino, and nitro.
  • R 4 is hydrogen and each of R 1 and R 2 is a methyl group or a hydrogen.
  • R 4 is hydrogen and R 3 is a six-member nitrogen containing a heterocyclyl group.
  • the nitrogen can be substituted with a phenylcarbonyl or benzylcarbonyl group, and the phenyl group can be optionally substituted with one or more fluorine atoms.
  • R 4 is hydrogen and R 3 is a (C 3 -C 10 )cycloalkyl or a (C 3 -C 10 )cycloalkyl(C 1 -C 3 )alkyl group. In a related embodiment, either R 1 or R 2 or both are hydrogen.
  • the compound is selected from the group consisting of
  • a method of treating presbyopia or cataract in a subject in need thereof comprising administering to the subject an effective amount of a composition comprising a compound having the formula (XIII)
  • R 1 at each position it occurs, is independently hydrogen or OR 2 , wherein R 2 is selected from the group consisting of hydrogen, (C 1 -C 3 )alkyl; halo(C 1 -C 3 )alkyl; (C 3 -C 7 )cycloalkyl; halo(C 3 -C 7 )cycloalkyl; phenyl(C 1 -C 3 )alkyl, aminophenyl(C 1 -C 3 )alkyl, and indanyl, wherein the phenyl or indanyl is optionally substituted with a halogen and the amino is optionally substituted with one or two (C 1 -C 3 )alkyl;
  • R 3 is selected from the group consisting of hydrogen, (C 1 -C 3 )alkyl; halo(C 1 -C 3 )alkyl; (C 3 -C 7 )cycloalkyl; halo(C 3 -C 7 )cycloalkyl; phenyl(C 1 -C 3 )alkyl, aminophenyl(C 1 -C 3 )alkyl, and indanyl, wherein the phenyl or indanyl is optionally substituted with a halogen and the amino is optionally substituted with one or two (C 1 -C 3 )alkyl;
  • R 4 at each position it occurs, is independently selected from the group consisting of hydrogen; halogen; (C 1 -C 3 )alkyl; halo(C 1 -C 3 )alkyl; (C 1 -C 3 )alkoxy; halo(C 1 -C 3 )alkoxy; OH, thiol, amino, and nitro;
  • n is an integer between 0 and 5;
  • n is an integer between 0 and 3.
  • R 2 and R 3 are methyl groups and n is 2 or 3.
  • R 4 is hydrogen.
  • the compound is selected from the group consisting of
  • a method of treating presbyopia or cataract in a subject in need thereof comprising administering to the subject an effective amount of a composition comprising a compound having the formula (XIV)
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, (C 1 -C 3 )alkyl; halo(C 1 -C 3 )alkyl; (C 3 -C 7 )cycloalkyl; halo(C 3 -C 7 )cycloalkyl; phenyl(C 1 -C 3 )alkyl, aminophenyl(C 1 -C 3 )alkyl, and indanyl, wherein the phenyl or indanyl is optionally substituted with a halogen and the amino is optionally substituted with one or two (C 1 -C 3 )alkyl; and R 3 CO, wherein R 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, and halo(C 3 -C 10 )cycloalkyl;
  • R 4 at each position that it occurs, is independently be selected from the group consisting of hydrogen; halogen; (C 1 -C 3 )alkyl; halo(C 1 -C 3 )alkyl; (C 1 -C 3 )alkoxy; halo(C 1 -C 3 )alkoxy; OH, thiol, amino, and nitro; and
  • R 5 is selected from the group consisting of hydrogen, (C 3 -C 10 )cycloalkyl; halo(C 3 -C 10 )cycloalkyl; (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl; halo(C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl; (C 1 -C 20 )alkyl; halo(C 1 -C 20 )alkyl; (C 3 -C 10 )heterocyclyl and halo(C 3 -C 10 )heterocyclyl, each optionally substituted at the heteroatom with R 6 CO, wherein R 6 is selected from the group consisting of (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, halo(C 3 -C 10 )cycloalkyl,
  • each of R 1 and R 2 is a hydrogen, methyl or a CH 3 CO group and R 4 is hydrogen.
  • each of R 1 and R 2 is a CH 3 CO group.
  • each of R 1 and R 2 is a CH 3 group.
  • each of R 1 and R 2 is a hydrogen.
  • R 5 is a hydrogen or a carboxyl group.
  • the compound is selected from the group consisting of
  • a method of treating presbyopia or cataract in a subject in need thereof comprising administering to the subject an effective amount of a composition comprising a compound having the formula (XV)
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, (C 1 -C 3 )alkyl; halo(C 1 -C 3 )alkyl; (C 3 -C 7 )cycloalkyl; halo(C 3 -C 7 )cycloalkyl; phenyl(C 1 -C 3 )alkyl, aminophenyl(C 1 -C 3 )alkyl, and indanyl, wherein the phenyl or indanyl is optionally substituted with a halogen and the amino is optionally substituted with one or two (C 1 -C 3 )alkyl;
  • R 3 at each position it occurs, is independently selected from the group consisting of hydrogen; halogen; (C 1 -C 3 )alkyl; halo(C 1 -C 3 )alkyl; (C 1 -C 3 )alkoxy; halo(C 1 -C 3 )alkoxy; OH, thiol, amino, and nitro;
  • R 4 is selected from the group consisting of (C 1 -C 3 )alkyl, OH, NR 5 R 6 , wherein each of R 5 and R 6 is independently selected from the group consisting of (C 1 -C 3 )alkyl; halo(C 1 -C 3 )alkyl, (C 3 -C 7 )cycloalkyl; halo(C 3 -C 7 )cycloalkyl; and phenyl(C 1 -C 3 )alkyl, wherein the phenyl is optionally substituted with halogen, (C 1 -C 3 )alkyl, or hydroxyl;
  • X is hydrogen or nitro
  • Y is H or CN.
  • R 1 and R 2 are hydrogen.
  • X can be a nitro group.
  • Y can be a cyano group.
  • R 4 can be NR 5 R 6 , R 5 being hydrogen.
  • R 4 can be an alkyl, a dialkylamine, or a hydroxyl.
  • the compound is one of
  • a method of treating presbyopia or cataract in a subject in need thereof comprising administering to the subject an effective amount of a composition comprising a compound having the formula (XVI)
  • R 1 is hydrogen or OR 3 , wherein R 3 is selected from the group consisting of hydrogen, (C 1 -C 3 )alkyl; halo(C 1 -C 3 )alkyl; (C 3 -C 7 )cycloalkyl; halo(C 3 -C 7 )cycloalkyl; phenyl(C 1 -C 3 )alkyl, aminophenyl(C 1 -C 3 )alkyl, and indanyl, wherein the phenyl or indanyl is optionally substituted with a halogen and the amino is optionally substituted with one or two (C 1 -C 3 )alkyl; and
  • R 2 at each position it occurs, is independently selected from the group consisting of hydrogen; halogen; (C 1 -C 3 )alkyl; halo(C 1 -C 3 )alkyl; (C 1 -C 3 )alkoxy; halo(C 1 -C 3 )alkoxy; OH, sulfonyl, thiol, amino, and nitro.
  • R 1 is hydrogen. In one embodiment, R 2 is hydrogen. In one embodiment, the compound is one of
  • a method of treating presbyopia or cataract in a subject in need thereof comprising administering to the subject an effective amount of a composition comprising a compound selected from the group consisting of
  • TTR transthyretin
  • R 1 is selected from the group consisting of
  • R 7 is (C 1 -C 6 )alkyl and R 8 is (C 1 -C 6 )alkyl, aryl, or a polyethylene glycol group.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • a method of treating Parkinson's disease in a subject in need thereof comprises administering to the subject an effective amount of a composition comprising a compound having the formula
  • R 1 is selected from the group consisting of
  • R 7 is (C 1 -C 6 )alkyl and R 8 is (C 1 -C 6 )alkyl, aryl, or a polyethylene glycol group.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • FIGS. 1A-1D show experimental results described in prior art.
  • FIGS. 1A and 1B depict graphs for stiffness of lens cortex and nucleus ( 1 A), and loss in accommodative power (diopters) ( 1 B) as a function of age. Graphs represent a summary of four separate studies on human accommodation.
  • FIG. 1C depicts mass distribution in the water-soluble fraction in young (19 years) (solid line and filled circle) and aged (83 years) (broken line and open circle) human lenses using SEC-MALS (multiangle light scattering).
  • FIG. 1D shows changes in the content of soluble AC (open circle) and high molecular weight protein (closed circle) in the lens nucleus as a function of age.
  • FIG. 2A shows the effect of exposing hAAC at 500 ug/ml to UVC.
  • FIG. 2B shows the effect of subjecting hAAC to Ca +2 /heat for 0, 5, 15 and 30 mins. Absorbance at 360/400 nm was measured at each time point. Mean ⁇ SEM of the measurements are shown.
  • FIGS. 3A and 3B show representative data for extent to which hAAC is protected by compounds (or DMSO control) from becoming aggregated. Aggregation was monitored for 120 minutes by absorbance at 360 nm for UV induced aggregation ( 3 A) or at 400 nm for heat induced aggregation ( 3 B). Mean ⁇ SEM of the measurements are shown.
  • FIGS. 4A-4F show structure activity relationship (SAR) based classification of compounds discovered from UV and heat induced hAAC aggregation assays.
  • Compounds are grouped into three series, Series-1: Macrocyclics; Series-2: “Covalent,” and Series-3: Catechols.
  • FIGS. 4A, 4C, and 4E show EC 50 curves for one compound, respectively, from the macrocyclic, covalent, and the catechol series.
  • FIGS. 4B, 4D, and 4F show percent protection from aggregation at 200 ⁇ M of compounds, respectively, from the macrocyclic, covalent, and the catechol series. Measurements for assessing protection were performed in triplicate.
  • FIG. 5 shows results of a biochemical test for target (i.e., hACC) engagement by SMD.
  • hACC 500 ug/ml
  • 200 ⁇ M CAP1613 and CAP1614 were treated overnight with 200 ⁇ M CAP1613 and CAP1614 and exposed to UV for 0, 5, 15 or 30.
  • Samples from each time point were run on a SDS-PAGE under non-reducing condition.
  • Insoluble and soluble HMW aggregates are shown by boxes at the top and bottom of the gel, respectively.
  • FIG. 6A shows sequence alignment of mammalian AACs. The conserved Cys (Cys131) is highlighted. Cys (Cys142), present only inhuman and chimpanzee, is also highlighted. A 3D model structure of hAAC (inset), showing the location of the residues Cys131 and Cys142, is shown to the right.
  • FIG. 6B shows reaction scheme for modification of cysteine with cysteine-reactive acrylamides (a) and chloro-acetamides (b).
  • FIG. 7A shows results for viability of HLE cells (B3 and SRA 01/04) exposed to UV (left) or heat (right), assessed 24 hours post-exposure by. Alamar blue was used for assessing viability. Mean ⁇ SEM of the measurements are shown.
  • FIG. 7B shows protection of SRA 01/04 cells (human lens epithelial cell line), pre-incubated with varying concentrations of compounds two hours prior to UV exposure. Relative protection was measured as percent viability compared to vehicle control 24 hours following UV exposure. Effect of compounds from each of three distinct chemical series (macrocyclics, covalent, and catechol) are shown. Mean ⁇ SEM of the measurements are shown.
  • FIG. 8A shows ectopic expression of AAC-EGFP in B-3 cells forms inclusions that co-localize with p62 (arrows).
  • FIG. 8B shows results of automated image analysis of >2500 cells. A statistically significant increase in GFP-positive inclusions due to AAC overexpression was observed. Mean ⁇ SEM of the measurements and p value (t test) are shown.
  • FIGS. 9A-9F show EC 50 curves of select compounds depicting the fold change in protection of hAAC against UVC and Ca +2 induced aggregation.
  • FIGS. 10A-10C are graphs showing dose-dependent protection of human lens epithelial cells (HLE) from UV-irradiation induced cell death.
  • SRA 01/04 HLE cells were pre-incubated for 3 hours with varying concentrations of compounds and exposed to UV light (9600 mJ/cm 2 , 254 nm). Percent viability was assessed by Alamar blue compared to non-irradiated controls after 24 hours. Mean ⁇ SD and linear regression curve fit produced with Graphpad software, and calculated EC50s ( ⁇ M) are provided.
  • FIGS. 11A-11D show the effect of CAP1159 on exposure of eye lens to UVC radiation.
  • the top row of the figure corresponds to lenses that were not exposed to UVC but contained same percent of DMSO as those that were exposed to UVC. The lenses were monitored and imaged for three days following the exposure to UVC. No drug was added to the lenses post UVC exposure.
  • the scale (0-9) for grading is shown in FIG. 11A .
  • FIG. 11C shows progression of cataract following UVC exposure over a period of three days.
  • FIG. 11D is a bar graph showing soluble protein content from treatment (CAP1159) and control groups as measured at 280 nm at the end of the three-day period. Lenses from each group were lysed and the supernatant pooled to measure the total soluble protein content from each group.
  • FIGS. 12A-12D show the effect of CAP1160 on exposure of eye lens to UVC radiation.
  • the top row of the figure corresponds to lenses that were not exposed to UVC but contained same percent of DMSO as those that were exposed to UVC. The lenses were monitored and imaged for three days following the exposure to UVC. No drug was added to the lenses post UVC exposure.
  • the scale (0-9) for grading is shown in FIG. 12A
  • FIG. 12C progression of cataracts following post UVC exposure as monitored over a period of three days.
  • FIG. 12D is a bar graph showing soluble protein content from treatment (CAP1160) and control groups as measured at 280 nm at the end of the three-day period. Lenses from each group were lysed and the supernatant pooled to measure the total soluble protein content from each group.
  • halo and “halogen” as used herein refer to an atom selected from fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), and iodine (iodo, —I).
  • alkyl used alone or as a part of a larger moiety such as e.g., “haloalkyl”, means a saturated monovalent straight or branched hydrocarbon radical having, unless otherwise specified, 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • “Monovalent” means attached to the rest of the molecule at one point.
  • cycloalkyl used alone or as part of a larger moiety, refers to a saturated cyclic aliphatic monocyclic, bicyclic or tricyclic ring system, as described herein, having from, unless otherwise specified, 3 to 10 carbon ring atoms.
  • Monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl.
  • Bicyclic cycloalkyl groups include e.g., cycloalkyl group fused to another cycloalkyl group, such as decalin or a cycloalkyl group fused to an aryl group (e.g., phenyl) or heteroaryl group, such as tetrahydronaphthalenyl, indanyl, 5,6,7,8-tetrahydroquinoline, and 5,6,7,8-tetrahydroisoquinoline.
  • aryl group e.g., phenyl
  • heteroaryl group such as tetrahydronaphthalenyl, indanyl, 5,6,7,8-tetrahydroquinoline, and 5,6,7,8-tetrahydroisoquinoline.
  • An example of a tricyclic ring system is adamantane.
  • bicyclic cycloalkyl groups can be either on the cycloalkyl portion or on the aryl group (e.g., phenyl) or heteroaryl group that results in a stable structure. It will be further understood that when specified, optional substituents on a cycloalkyl may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl is attached.
  • heterocyclyl means a 4-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S.
  • heterocycle means “heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclic moiety”, and “heterocyclic radical”, may be used interchangeably.
  • a heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxetanyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and tetrahydropyrimidinyl.
  • a heterocyclyl group may be mono- or bicyclic.
  • bicyclic heterocyclyl groups include, e.g., unsaturated or saturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aromatic or heteroaryl ring, such as for example, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, tetrahydronaphthyridinyl, indolinonyl, dihydropyrrolotriazolyl, imidazopynmidinyl, quinolinonyl, dioxaspirodecanyl. It will be understood that the point of attachment for bicyclic heterocyclyl groups can be on the heterocyclyl group or aromatic ring that results in a stable structure. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached.
  • heteroaryl used alone or as part of a larger moiety as in “heteroarylalkyl”, “heteroarylalkoxy”, or “heteroarylaminoalkyl”, refers to a 5-10-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S and includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”.
  • heteroaryl and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, and quinoxalinyl.
  • a heteroaryl group may be mono- or bicyclic.
  • aryl refers to a 6-14 membered aromatic ring containing only ring carbon atoms.
  • the aryl ring may be monocyclic, bicyclic or tricyclic. Non-limiting examples include phenyl, naphthyl or anthracenyl, and the like. It will also be understood that when specified, optional substituents on an aryl group may be present on any substitutable position. In an embodiment, the aryl group is unsubstituted or mono- or di-substituted.
  • the terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like).
  • the subject is a human in need of treatment.
  • the compounds of the invention may be present in the form of pharmaceutically acceptable salts.
  • the salts of the compounds of the invention refer to non-toxic “pharmaceutically acceptable salts.”
  • Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • Pharmaceutically acceptable basic/cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.
  • Pharmaceutically acceptable acidic/anionic salts include, e.g., the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, carbonate, citrate, dihydrochloride, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, malate, maleate, malonate, mesylate, nitrate, salicylate, stearate, succinate, sulfate, tartrate, and tosylate.
  • Methods used to deliver compounds described herein to the eye include topical, subconjunctival, intravitreal, and systemic.
  • Topical ocular drug administration is typically accomplished by eye drops. Contact time on the eye surface is short, but can be prolonged using specific formulations, e.g., gels, gelifying formulations, ointments, and inserts.
  • specific formulations e.g., gels, gelifying formulations, ointments, and inserts.
  • the basic nature of the solution containing the drug composition is aqueous and as such, agents designed to increase the viscosity of the solution may be employed.
  • agents include, for example, hydroxypropyl methylcellulose, carbopol, polyvinyl alcohol, and the like.
  • Subconjunctival administration Traditionally subconjunctival injections have been used to deliver drugs at increased levels to the uvea. This mode of administration can be used to deliver drugs in controlled release formulations to the posterior segment and to guide the healing process after surgery.
  • Intravitreal administration Direct drug administration into the vitreous offers the advantage of more straightforward access to the vitreous and retina. Delivery from the vitreous to the choroid is more complicated, however, due to the hindrance by the RPE (Retinal Pigment Epithelium) barrier. Small molecules are able to diffuse rapidly in the vitreous but the mobility of large molecules, particularly positively charged, is restricted.
  • An injectable composition suitable for intraocular injection typically comprises a solution of the drug or a fine particle suspension, which may enable sustained delivery to the eye.
  • Formulations are usually aqueous and may commonly include solubilization enhancers such as, but not limited to, polyvinyl alcohol, Tween 80, solutol, cremophore, and cyclodextrin.
  • the formulation is typically in the pH range of 3-8, which is be regarded as acceptable for intravitreal formulations.
  • buffering systems are sometimes used. These include but are not limited to citrate and phosphate based buffering systems.
  • the tonicity of the intravitreal formulation may be adjusted to remain within a desirable range which typically would be 250-360 mOsm/kg. Adjustment of tonicity may be achieved for example by addition of sodium chloride.
  • intravitreal formulations are produced by sterile manufacture for single use. Preserved formulations can be used, for example formulations containing a preservative such as benzoyl alcohol.
  • the dose of the active agent in the compositions of the invention will depend on the nature and degree of the condition, the age and condition of the patient and other factors known to those skilled in the art. Administration can be either as a single injection with no further dosing or multiple injections.
  • Systemic medication is required for posterior segment therapy and to complement topical therapy for the anterior segment.
  • the posterior segment always requires systemic therapy, because most topical medications do not penetrate to the posterior segment.
  • Retrobulbar and orbital tissues are treated systemically.
  • the present technology provides a method of treating presbyopia or cataract, the method requiring administration of an effective amount of a composition comprising a compound described herein, the compound being present in a prodrug form, or being converted to a prodrug form.
  • Prodrug formulations use pharmacologically inactive derivatives of drug molecules that are better able to penetrate the cornea (e.g., they are more lipophilic) than the standard formulation of the drug. See review by Brian G. Short, Toxicologic Pathology, 36:49-62, 2008. As described in the review and the references cited therein, within the cornea or after corneal penetration, the prodrug is either chemically or enzymatically metabolized to the active parent compound. Enzyme systems identified in ocular tissues include esterases, ketone reductase, and steroid 6 ⁇ -hydroxylase.
  • prodrugs are delivered conventionally by topical application such as antiviral prodrugs ganciclovir and acyclovir, although ganciclovir has also been delivered intravitreally by injection or as a nonbiodegradable reservoir (see below).
  • Delivery of a drug with a nonnatural enzyme system in the cornea has been achieved with topical 5-flurocytosine, a prodrug of 5-fluorouracil, administered after subconjunctival transplantation of cells containing the converting enzyme cytosine deaminase.
  • Increased corneal penetration into the anterior segments can be achieved with the addition of permeability enhancers to the drug formulation.
  • Surfactants, bile acids, chelating agents, and preservatives have all been used.
  • Cyclodextrins cylindrical oligonucleotides with a hydrophilic outer surface and a lipophilic inner surface that form complexes with lipophilic drugs, are among the more popular permeability enhancers. They increase chemical stability and bioavailability and decrease local irritation, and they have been used with corticosteroids, choloramphenicol, diclofenac, cyclosporine, and sulfonamide carbonic anhydrase inhibitors.
  • the present invention includes small molecule disaggregases (SMDs) that are synthesized as prodrugs such that they have a better ability to permeate the cornea.
  • SMDs small molecule disaggregases
  • Example 1 Recombinant hAAC Forms HMW Aggregates Upon Exposure of UV and Heat
  • the factors that contribute to the age-related loss of soluble functional AAC includes post translational modification of amino-acid residues due to exposure to UV and heat. Therefore, to identity potent SMDs, experimental conditions were developed under which hAAC, when exposed to UV-C radiation or heated to 50° C., formed HMW aggregates ( FIGS. 2A-2D ). Consistent with published reports, hAAC HMW aggregates formed under UV-C radiation remain insoluble compared to the heat induced HMW ( FIGS. 2C & 2D ). The system described herein recapitulates the factors that contribute to formation of presbyopia.
  • the biochemical screening method (i) be based on non-enzymatic conditions that contribute to the loss of function of AAC and formation of HMW aggregates, and (ii) uses relevant species of AAC, particularly since human AAC contains a unique cysteine residue (Cys142). Accordingly, the screening method employed here has taken these factors into consideration.
  • each compound at 200 ⁇ M concentration (0.5% DMSO) was incubated with hAAC (500 ug/ml for UV and 400 ug/ml for heat induced aggregation) for 30 mins at room temperature and absorbance measured at multiple time points (0, 30, 60, 90 and 120 minutes).
  • hAAC 500 ug/ml for UV and 400 ug/ml for heat induced aggregation
  • absorbance measured at multiple time points (0, 30, 60, 90 and 120 minutes).
  • Compounds showing greater than 50% protection relative to untreated were retested and rank ordered to provide dose dependent EC 50 value measurements. Table 2 below shows distribution of compounds and the extent to which they protect hAAC from aggregating.
  • Structural analysis of the SMDs identified revealed that compounds that protect against aggregation of hAAC under UV exposure can be grouped into two classes, namely macrocyclics and “covalent”, and those that protect against heat induced aggregation as catechols.
  • the molecular structures of the hits for each series, along with their percent protection, are shown in FIGS. 4A-4F .
  • Dose-dependent potency curve and EC 50 value for one compound from each series are also shown.
  • the fact that the SMDs identified prevent the aggregation of hAAC when exposed to UV demonstrate their ability to directly engage hAAC.
  • Example 3 SMDs Forming Covalent Bond with ACC Prevent HMW hAAC Aggregate Formation
  • AAC contains two cysteine residues which are known to undergo post translational modification to form intra/intermolecular disulfide bonds resulting in HMW aggregates.
  • disulfide bonds could be prevented using a structure-guided design employing covalent bond forming cysteine-reactive drug-like compounds targeting the two cysteines in order to develop potent and selective SMDs of hAAC.
  • irreversible electrophile cysteine-reactive compounds comprising acrylamides and chloro-acetamides functional groups were included in screening assays for SMDs. These compounds were made using the synthesis route shown below in Scheme 1.
  • FIGS. 4C-4D The screening resulted in the identification of multiple compounds ( FIGS. 4C-4D ). These compounds are referred to as “covalent” given their potential to from covalent bond with the cysteine residue ( FIGS. 6A and 6B ).
  • Example 4 Cell Based Assays Using Human Lens Epithelial (HLE) Cells
  • FIGS. 7A and 7B Cell-based using assays using human lens epithelial cell lines SRA 01/04 and B3 were also performed. The cells were exposed to UV or heat and cell viability assessed 24 hours post-exposure by Alamar blue staining. The results are shown in FIGS. 7A and 7B .
  • SRA 01/04 cells were pre-incubated with varying concentrations of compounds two hours prior to UV exposure. Relative protection was measured as percent viability compared to vehicle control 24 hours following UV exposure. Effect of compounds from each of three distinct chemical series (macrocyclics, covalent, and catechol) are shown in FIG. 7B . Mean ⁇ SEM of the measurements are shown.
  • Ectopic expression of AAC-EGFP in B-3 cells shows that AAC forms inclusions that co-localize with p62 (arrows) ( FIG. 8A ).
  • Automated image analysis of >2500 cells is shown in FIG. 8B .
  • a statistically significant increase in GFP-positive inclusions due to AAC overexpression was observed.
  • Mean ⁇ SEM of the measurements and p value (t test) are shown. The results show that high-content screening could be used to evaluate the cellular pharmacodynamic effects of SMDs for measuring cellular aggregates of AAC.
  • Catechol derivatives described herein can be synthesized using the reaction schemes shown below. Specific examples of the derivatives synthesized are described following the reaction schemes.
  • Reagents and conditions for scheme 1 (a) Grignard Reaction conditions, Diethylether, 0° C. to r.t.; (b)oxidation, PCC, CH 2 Cl 2 , r.t., (c) Pd/C, H 2 , methanol, r.t.; (d) 70% HNO 3 , r.t.; (e) BBr 3 , CH 2 Cl 2 , r.t.; (f) PEG-acid, EDC, DMAP, r.t.
  • R 6 , R 7 , R 8 , R 9 , and R 10 can independently be, for example, H, alkyl, aryl, halogen, nitro, amino, trifluoromethyl, and trifluoromethoxy.
  • R 17 , R 18 , and R 19 can independently be, for example, H, alkyl, aryl, halogen, nitro, amino, methoxy, trifluoromethyl and trifluoromethoxy.
  • R 20 can be an alkyl or an aryl group.
  • Reagents and conditions for scheme 3 (h) EDC, HOBt, DIEA, DMF, rt, 16 h; (i) TFA, CH 2 Cl 2 , rt, 6 h; (j), Aryl amines, EDC, HOBt, DIEA, DMF, rt, 20 h.
  • R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , and R 25 can, for example, independently be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, and trifluoromethyl.
  • Scheme 4 Reagents and conditions for scheme 4: (k) EDC, HOBt, DIEA, DMF, rt, 15 h; (1) TFA, CH 2 Cl 2 , rt, 6 h; (m) R 26 —CO 2 H, EDC, HOBt, DIEA, DMF, rt, 22 h.
  • R 17 , R 18 , and R 19 can, for example, independently be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, and trifluoromethyl.
  • R 26 can be an alkyl or an aryl group.
  • CAP1226 was synthesized using the appropriate reagents and starting materials as shown in Scheme 2 above. Briefly, a mixture of 3,4-dimethoxyphenethylamine (1 mmol), cyclobutanecarboxylic acid (1 mmol), EDC (1.2 mmol), HOBt (1.2 mmol), and DIEA (1.5 mmol) in DMF (3 mL) were stirred for 16 h at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate solution, water, and brine respectively. The organic layer was dried over magnesium sulfate and concentrated in vacuo.
  • CAP1225 was prepared using scheme 2 shown above. The compound was characterized by NMR and Mass spectroscopy.
  • CAP1227 was prepared using scheme 2 shown above. The compound was characterized by NMR and Mass spectroscopy.
  • CAP1228 was prepared using scheme 3 shown above. The compound was characterized by NMR and Mass spectroscopy.
  • CAP1230 was prepared using scheme 2 shown above. The compound was characterized by NMR and Mass spectroscopy.
  • CAP1231 was prepared using scheme 2 shown above. The compound was characterized by NMR and Mass spectroscopy.
  • CAP1232 was prepared using scheme 2 shown above. The compound was characterized by NMR and Mass spectroscopy.
  • Table 3 lists select catechol derivatives and their effectiveness in preventing Ca +2 and UVC induced aggregation of alpha-A crystalline.
  • Table 4 below provides EC 50 values of select catechol derivatives in preventing Ca +2 and UVC induced aggregation of alpha-A crystalline.
  • Table 5 lists select tolcapone derivatives and their effectiveness in preventing UV-and heat induced aggregation of alpha-A crystalline.
  • topical administration is the preferred route for ophthalmic drugs due to its localized drug action at anterior segment of the eye.
  • poor penetration and rapid loss of therapeutics following its topical administration are the major restrictions of the topical route.
  • the problem is further amplified and compounded if the given drug has poor aqueous solubility.
  • Formulation approach has been extensively used to address and overcome the poor ocular bioavailability.
  • chemical approach such as prodrug has been utilized to optimize physicochemical and biochemical properties of a drug molecule for increasing its ocular bioavailability.
  • An essential step in effective prodrug therapy is the activation of the prodrug and the release of the free active therapeutic agent.
  • Important enzymes involved in the activation and bioconversion of prodrugs include phosphatase, paraoxonase, carboxylesterase, acetylcholinesterase, and cholinesterase.
  • tolcapone is associated with side effects, particularly liver injury. Improving solubility of tolcapone, for example, by administering it as a prodrug can lead to the drug being effective at lower doses.
  • a prodrug of tolcapone CAP4196 was synthesized. It is believed that increased solubility of the prodrug would lead to a more effective treatment of and ocular diseases (presbyopia or cataract), Parkinson's disease, Amyloid diseases, and prevention and/or treatment of transthyretin (TTR)-associated amyloidosis.
  • TTR transthyretin
  • Solubility The solubility of CAP1160 and CAP4196 was tested with different FDA approved excipients such as cyclodextrin, PEG-b-PCL, Kolliphor-EL, Kolliphor-40, sorbitol, propelyne gycol, sodium phosphate, etc. Only a 10-fold improvement (1.5 mg/ml) in the solubility of CAP1160 was observed with (2-hydroxypropyl)-beta-cyclodextrin. On the other hand, CAP4196, the phosphate prodrug demonstrated greater than 660-fold improvement (100 mg/ml) in solubility with only water as solvent and the pH of the formulation was 6.65, which is within the pH range of the tears (6.5-7.6). This makes the formulation safe for topical use (see Table 6).
  • Solubility of CAP1160 and CAP4196 FDA approved excipients Solubility in water mg/ml 0.1 100 Solubility in water with (2-hydroxypropyl)-beta 2 100 cyclodextrin mg/ml (1:1) With PEG-b-PCL (1:1) mg/ml in water 1 ND With Kolliphor 40 (1:1) In water 1 ND
  • Example 9 Ocular Safety in New Zealand White Rabbits (NZWR) with Repeated Dose of Prodrug CAP4196 for 7 Days
  • Prodrug CAP4196 is well-tolerated up to 10% concentration in New Zealand white rabbits.
  • Initial maximum tolerated dose studies (MTD) help identify observable signs of toxicity and provide a rationale for setting dose levels in later definitive studies. Therefore, the MTD of CAP4196 was evaluated in New Zealand white rabbits.
  • Four animals per group were dosed with increasing concentrations (0.25, 2.5, 8 and 10%) of CAP4196 at 50 ⁇ l volume q.i.d. dosing at 2 hrs interval. Following the dosing, the animals were evaluated for mortality and morbidity, ophthalmological examination, body weight, and clinical pathology before start of dosing then on dosing days 2, 4, and 6 prior to first dose instillation and on day 7, one hour after last dose instillation.
  • Transthyretin is a plasma homotetrameric protein with a role in fatal systemic Amyloidosis (Sant'Anna, R. et al. (2016) Nat. Commun. 7:10787 doi: 10.1038/ncomms10787). TTR tetramer dissociation precedes pathological TTR aggregation. Native state
  • Tolcapone an FDA-approved molecule for Parkinson's disease, is a potent TTR aggregation inhibitor (Sant'Anna, R. et al. (2016)). Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity ((Sant'Anna, R. et al. (2016). As such, tolcapone believed to be a strong candidate for treating TTR amyloidosis.
  • tolcapone use is associated with side effects, particularly liver injury, and improving solubility of tolcapone, for example, by administering it as a prodrug can lead to the drug being effective at lower dose, it is contemplated that prodrugs of tolcapone described herein would be better as therapeutics against TTR amyloidosis and Parkinson's disease.

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Abstract

Methods of treating presbyopia or cataract in a subject in need thereof are provided. The methods require administering to the subject an effective amount of a composition comprising a compound that inhibits the formation of high molecular weight aggregates of human α-A-crystallin. Compositions containing certain compounds are believed to be also effective in the treatment of transthyretin (TTR)-associated amyloidosis and Parkinson's disease.

Description

    CROSS REFERENCES TO RELATED APPLICATIONS
  • This application claims the benefit of U.S. Provisional Application No. 62/653,249 filed Apr. 5, 2018, and U.S. Provisional Application No. 62/694,729 filed Jul. 6, 2018, which are both hereby incorporated by reference in their entireties.
    • BACKGROUND
  • Presbyopia is the loss of accommodative ability of the eye resulting in the inability to focus on near objects. Presbyopia affects everyone over the age of 45 and has significant negative impacts on the quality of life. Current treatments for presbyopia include: (i) non-invasive approaches that utilize devices to help improve near and distance vision but do nothing to restore the natural process of accommodation and require constant use of the devices, and (ii) invasive surgical procedures which are associated with major complications including decrease in vision quality, regression effects, anisometropia, corneal ectasia, and haze. Most importantly, none of these methods can reverse presbyopia. Moreover, no treatment option exists that can either prevent or delay the onset of presbyopia.
  • Stiffening of eye lens, and changes in the elasticity of the lens capsule, dimension of eye lens, dimension of the zonular attachment, and ciliary muscle (CM) contractions, have all been proposed as contributing factors for presbyopia. However, human and non-human primate studies suggest that CM function is normal well beyond the onset of presbyopia. By contrast, the human lens increases in stiffness with age in a manner that directly correlates with a loss in accommodative power (FIG. 1). The loss in accommodative power can be restored by implanting intraocular lenses made from a flexible polymer suggesting that restoration of lens flexibility is sufficient to restore accommodation. Therefore, a pharmacological agent that could prevent or reverse the hardening of the crystalline lens would provide a promising avenue for a novel non-invasive treatment for presbyopia.
  • At the molecular level, proteins known as crystallins play a major role in the stiffening of the eye lens. The lens crystallins comprise three isoforms, α, β, and γ and make up 90% of the eye lens protein content. α crystalline (AC), an ATP-independent chaperone and member of the small heat shock protein (sHsp) family, constitutes 40% of the crystallin protein content. It exists as a hetero-oligomer of two subunits, αA-crystallin (AAC) and αB-crystallin (ABC) and its expression is primarily restricted to the eye lens. It recognizes exposed conformational features in partially unfolded lens proteins and sequesters them from one another, thereby reducing the population of aggregation-prone species that would otherwise lead to various age-related vision impairment.
  • Multiple studies have established a link between stiffening of the human lens and AC function. Dynamic mechanical analysis measurements have shown that there is a significant increase in the stiffness of the lens with age, particularly in the lens nucleus where a 500- to 1000-fold decrease in elasticity is observed (FIG. 1A). This increase in lens stiffness correlates with the age-related decline in free AC chaperone concentration as most AC becomes incorporated into high molecular weight (HMW) aggregates by the age of 40-50 (FIG. 2). This conversion of soluble AC into HMW aggregates is accompanied by a large increase in lens stiffness (FIG. 1A), presumably because the low level of soluble AC present is not sufficient to chaperone denatured proteins. That age-related decrease in free AC chaperone is responsible for lens stiffness is supported by experiments where human lenses were subjected to heating to mimic the age-related conversion of soluble AC into HMW aggregates and an increase in lens stiffness was observed. Similarly, purified soluble AC forms HMW aggregates when exposed to UV radiation with a loss in chaperone like activity. The HMW aggregate is formed due to the intermolecular cross-linking, particularly S—S bonds, resulting from the oxidation of cysteine sulfhydryl groups (—SH). The formation of this disulfide cross-linked HMW aggregate is thought to be a major contributor in increasing the stiffness and loss of accommodation amplitude of the lens.
  • It has been suggested that presbyopia is the earliest observable symptom of age-related nuclear (ARN) cataract, a major cause of blindness in the world.
  • Given the need for noninvasive treatment that can protect and restore the accommodative ability of the eye lost in presbyopia and given that formation of HMW AC aggregates is a major causative factor underlying presbyopia, there is a need for the development of pharmacological agents that can selectively delay and/or reverse the HMW AC aggregate formation.
    • SUMMARY OF THE INVENTION
  • Provided herein is a rational structure activity relation-based approach for identifying small molecule disaggregases (SMDs) that can inhibit formation of HMW aggregates human ACC (hAAC). Several SMDs were identified based on this approach. It is believed that these SMDs are useful for the treatment of presbyopia, and for the treatment of cataract. The cataract can be age-related (nuclear sclerotic, cortical, and posterior subcapsular), congenital, secondary, traumatic and radiation cataracts.
  • In one aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula (VII)
  • Figure US20210154213A1-20210527-C00001
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
  • R1 is independently selected from the group consisting of hydrogen; (C1-C3)alkyl; halo(C1-C3)alkyl; (C3-C6)cycloalkyl; halo(C3-C6)cycloalkyl; (C1-C3)alkyloxy; and R4C═O; wherein R4 is selected from the (C1-C6)alkyl; halo(C1-C6)alkyl; (C3-C6)cycloalkyl; halo(C3-C6)cycloalkyl; aryl; haloaryl; and
  • Figure US20210154213A1-20210527-C00002
  • wherein R7 is (C1-C6)alkyl and R8 is (C1-C6)alkyl, aryl, or a polyethylene glycol group;
  • R2 is independently selected from the group consisting of hydrogen, R5, OR5, N(R5)(R6), halide, CN, NO2, C(O)OR5, CON(R5)(R6), S(O)NR5 2, SO3H, SO2CH3, phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R5 and R6 are independently selected from hydrogen atom, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, and (C3-C6)cycloalkylhalo(C1-C6)alkyl groups; wherein R2 can occupy 0-2 positions in the ring of its occurrence; and wherein, in the event any two adjacent groups selected are OR5 groups, the two OR5 groups may optionally be cross-linked via their R5 functionalities to form an additional ring; and
  • R3 is selected from the group consisting of hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, and hydroxy(C2-C6)alkenyl.
  • In one embodiment of the method requiring the compound having formula (VII), the compound is
  • Figure US20210154213A1-20210527-C00003
  • wherein
  • R1 is selected from the group consisting of
  • Figure US20210154213A1-20210527-C00004
  • wherein R7 is (C1-C6)alkyl and R8 is (C1-C6)alkyl, aryl, or a polyethylene glycol group.
  • In one embodiment of the method requiring the compound having formula (VII), each R1 is a hydrogen atom. In another embodiment, each R1 is an alkyl. In yet another embodiment, one R1 is a hydrogen or an alkyl, and the other R1 is a carboxyl, benzoxyl, or a methoxyl. In one embodiment, the compound is
  • Figure US20210154213A1-20210527-C00005
    Figure US20210154213A1-20210527-C00006
  • In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula (I)
  • Figure US20210154213A1-20210527-C00007
  • or a solvate or a pharmaceutically acceptable salt thereof,
  • wherein
  • R1 is R8 or R8C═O, wherein R8 is selected from hydrogen, (C1-C6)alkyl and (C3-C6)cycloalkyl groups, wherein the alkyl and the cycloalkyl groups are optionally substituted with one or more fluorine atoms;
  • R2 is aryl, (C1-C3)alkylaryl, heteroaryl, (C1-C3)alkylheteroarylalkyl, (C1-C3)alkylheterocyclyl, each of which is optionally substituted with up to 3 groups independently selected from R11;
  • R3, R4, R5, R6, and R7, are independently selected from hydrogen, R9, OR9, N(R9)(R10), halogen, CN, NO2, C(O)OR9, CON(R9)(R10), S(O)NR9 2, SO3H, SO2CH3, phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R9 and R10 are independently selected from hydrogen atom, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, and (C3-C6)cycloalkylhalo(C1-C6)alkyl groups; wherein R3, R6, and R7 can occupy 0-2 positions in their respective rings; and wherein, in the event any two adjacent groups selected from R3, R4, R5, R6, and R7 are OR9 groups, the two OR9 groups may optionally be cross-linked via their R9 functionalities to form an additional ring; and
  • R11 is selected from the group consisting of oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C1-C6)alkylheteroaryl, halo(C1-C6)alkylheteroaryl, hydroxy(C1-C6)alkylheteroaryl, (C3-C6)cycloalkylheteroaryl, halo(C3-C6)cycloalkylheteroaryl, hydroxy(C3-C6)cycloalkylheteroaryl, heterocyclylheteroaryl, (C1-C6)alkyl heterocyclylheteroaryl, halo(C1-C6)alkyl heterocyclylheteroaryl, hydroxy(C1-C6)alkyl heterocyclylheteroaryl, heteroalkyl, heterocyclylalkyl, (CH2)1-3COOH, (C1-C3)alkylcarbonyloxy, (C3-C6)cycloalkyl(C1-C6)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkoxy, (C3-C6)cycloalkyl(C1-C6)alkoxy, halo(C1-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C3-C6)cycloalkyl(C1-C6)alkoxy, (C1-C6)alkylthio, (C3-C6)cycloalkythio, (C3-C6)cycloalkyl(C1-C6)alkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C3-C6)cycloalkyl(C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C3-C6)cycloalkylsulfinyl, (C3-C6)cycloalkyl(C1-C6)alkylsulfinyl, halo(C1-C6)alkylsulfinyl, halo(C3-C6)cycloalkylsulfinyl, halo(C3-C6)cycloalkyl(C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C3-C6)cycloalkylsulfonyl, (C3-C6)cycloalkyl(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyl, halo(C3-C6)cycloalkylsulfonyl, halo(C3-C6)cycloalkyl(C1-C6)alkylsulfonyl, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, and (C1-C3)alkoxy(C1-C3)alkylaminocarbonyl.
  • In one embodiment of the method requiring the compound having formula (I), R7 is hydrogen. In another embodiment R6 is hydrogen. In yet another embodiment, R3 is hydrogen.
  • In one embodiment, R5 is hydrogen. In one embodiment, R4 is hydrogen. In one embodiment, R2 is a heteroaryl having one ring nitrogen. In one embodiment, R2 is a heteroaryl having two ring nitrogen atoms. In one embodiment, R2 is a heteroaryl having one or two ring nitrogen, the ring optionally substituted with up to two (C1-C6)alkyl groups. In one embodiment, R2 is a heteroaryl having one or two ring nitrogen, the ring optionally substituted with up to two (C1-C6)alkyl groups and an oxo group. In one embodiment, the compound is one of
  • Figure US20210154213A1-20210527-C00008
  • In yet another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula (II)
  • Figure US20210154213A1-20210527-C00009
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
  • X is CH2 or C═O
  • n is 1 or 2
  • R1, R4, and R5 are independently selected from hydrogen, R6, OR6, N(R6)(R7), halide, CN, NO2, C(O)OR6, CON(R6)(R7), S(O)NR6 2, SO3H, SO2CH3, phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R6 and R7 are independently selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, and (C3-C6)cycloalkylhalo(C1-C6)alkyl groups; wherein R1, R4, and R5 can occupy 0-2 positions in their respective ring; and wherein, in the event any two adjacent groups selected from R1, R4, and R5, are OR6 groups, the two OR6 groups may optionally be cross-linked via their R6 functionalities to form an additional ring; and
  • R2 is selected from the group consisting of hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, and (C1-C6)alkoxy(C1-C6)alkyl group;
  • R3 is aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with up to 3 groups independently selected from R8; and
  • R8 is selected from the group consisting of oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C1-C6)alkylheteroaryl, halo(C1-C6)alkylheteroaryl, hydroxy(C1-C6)alkylheteroaryl, (C3-C6)cycloalkylheteroaryl, halo(C3-C6)cycloalkylheteroaryl, hydroxy(C3-C6)cycloalkylheteroaryl, heterocyclylheteroaryl, (C1-C6)alkyl heterocyclylheteroaryl, halo(C1-C6)alkyl heterocyclylheteroaryl, hydroxy(C1-C6)alkyl heterocyclylheteroaryl, heteroalkyl, heterocyclylalkyl, (CH2)1-3COOH, (C1-C3)alkylcarbonyloxy, (C3-C6)cycloalkyl(C1-C6)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkoxy, (C3-C6)cycloalkyl(C1-C6)alkoxy, halo(C1-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C3-C6)cycloalkyl(C1-C6)alkoxy, (C1-C6)alkylthio, (C3-C6)cycloalkythio, (C3-C6)cycloalkyl(C1-C6)alkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C3-C6)cycloalkyl(C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C3-C6)cycloalkylsulfinyl, (C3-C6)cycloalkyl(C1-C6)alkylsulfinyl, halo(C1-C6)alkylsulfinyl, halo(C3-C6)cycloalkylsulfinyl, halo(C3-C6)cycloalkyl(C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C3-C6)cycloalkylsulfonyl, (C3-C6)cycloalkyl(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyl, halo(C3-C6)cycloalkylsulfonyl, halo(C3-C6)cycloalkyl(C1-C6)alkylsulfonyl, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, and (C1-C3)alkoxy(C1-C3)alkylaminocarbonyl.
  • In one embodiment of the method requiring the compound having formula (II), R1 is a (C3-C6)cycloalkyl, and substitutes one or two ring hydrogen atoms. In one embodiment, R1 is a cyclopropyl, and substitutes one ring hydrogen atom. In one embodiment, R1 is a (C3-C6)cycloalkyl(C1-C6)alkyl. In one embodiment, R1 is cyclopropylmethyl. In one embodiment, R5 is hydrogen. In one embodiment, R5 is hydrogen, and R1 is a (C3-C6)cycloalkyl, and substitutes one or two ring hydrogen atoms. In one embodiment, R5 is hydrogen and R1 is a (C3-C6)cycloalkyl(C1-C6)alkyl. In one embodiment, X is CH2 and R2 is (C1-C6)alkoxy(C1-C6)alkyl group. In one embodiment, R3 is an aryl. In one embodiment, R3 is a heteroaryl. In one embodiment, the compound is one of
  • Figure US20210154213A1-20210527-C00010
  • In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula (III)
  • Figure US20210154213A1-20210527-C00011
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
  • X is N;
  • p is 0 or 1;
  • n is 0, 1, or 2;
  • R1, R4, and R5 are independently selected from hydrogen R6, OR6, N(R6)(R7), halide, CN, NO2, C(O)OR6, CON(R6)(R7), S(O)NR6 2, SO3H, SO2CH3, phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R6 and R7 are independently selected from hydrogen atom, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, and (C3-C6)cycloalkylhalo(C1-C6)alkyl groups; wherein R1, R4, and R5 can occupy 0-2 positions in their respective ring; and wherein, in the event any two adjacent groups selected from R1, R4, and R5, are OR6 groups, the two OR6 groups may optionally be cross-linked via their R6 functionalities to form an additional ring;
  • R2 is selected from the group consisting of hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, and (C1-C6)alkoxy(C1-C6)alkyl;
  • R3 is one of hydrogen, R8 and SO2R8, wherein R8 is selected from the group consisting of aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with up to 3 groups independently selected from R9;
  • R9 is selected from the group consisting of oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C1-C6)alkylheteroaryl, halo(C1-C6)alkylheteroaryl, hydroxy(C1-C6)alkylheteroaryl, (C3-C6)cycloalkylheteroaryl, halo(C3-C6)cycloalkylheteroaryl, hydroxy(C3-C6)cycloalkylheteroaryl, heterocyclylheteroaryl, (C1-C6)alkyl heterocyclylheteroaryl, halo(C1-C6)alkyl heterocyclylheteroaryl, hydroxy(C1-C6)alkyl heterocyclylheteroaryl, heteroalkyl, heterocyclylalkyl, (CH2)1-3COOH, (C1-C3)alkylcarbonyloxy, (C3-C6)cycloalkyl(C1-C6)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkoxy, (C3-C6)cycloalkyl(C1-C6)alkoxy, halo(C1-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C3-C6)cycloalkyl(C1-C6)alkoxy, (C1-C6)alkylthio, (C3-C6)cycloalkythio, (C3-C6)cycloalkyl(C1-C6)alkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C3-C6)cycloalkyl(C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C3-C6)cycloalkylsulfinyl, (C3-C6)cycloalkyl(C1-C6)alkylsulfinyl, halo(C1-C6)alkylsulfinyl, halo(C3-C6)cycloalkylsulfinyl, halo(C3-C6)cycloalkyl(C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C3-C6)cycloalkylsulfonyl, (C3-C6)cycloalkyl(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyl, halo(C3-C6)cycloalkylsulfonyl, halo(C3-C6)cycloalkyl(C1-C6)alkylsulfonyl, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, and (C1-C3)alkoxy(C1-C3)alkylaminocarbonyl.
  • In one embodiment of the method requiring the compound having formula (III), R1 is hydrogen. In one embodiment, R1 is hydrogen and each of p and n is zero. In one embodiment, X is N. In one embodiment, X is N and R2 is a cyclopropyl. In one embodiment, each of R1, R4 and R5 are hydrogen. In one embodiment, R3 is a heteroaryl group. In one embodiment, R3 is a heteroaryl substituted with a heterocyclyl group. In one embodiment, R3 is SO2R8, wherein R8 is a heteroaryl. In one embodiment, the compound is one of
  • Figure US20210154213A1-20210527-C00012
  • In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula (IV)
  • Figure US20210154213A1-20210527-C00013
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
  • R1 and R3 are independently hydrogen, (C1-C3)alkyl, halo(C1-C3)alkyl, (C3-C6)cycloalkyl, and halo(C3-C6)cycloalkyl;
  • R2 is selected from the group consisting of hydrogen, (C1-C3)alkyl, halo(C1-C3)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, and R5C═O, wherein R5 is selected from the (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, aryl, and haloaryl;
  • X is O, S, or NH; and
  • R4 is selected from the group consisting of hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, and hydroxy(C2-C6)alkenyl.
  • In one embodiment of the method requiring the compound having formula (IV), X is O. In one embodiment, X is NH. In one embodiment, X is NH and R4 is (C2-C6)alkenyl. In one embodiment, R1 is a methyl. In one embodiment, R2 is hydrogen. In one embodiment, R3 is methyl. In one embodiment, the compound is one of
  • Figure US20210154213A1-20210527-C00014
  • In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula (V)
  • Figure US20210154213A1-20210527-C00015
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
  • R1 is independently selected from hydrogen, R5, OR5, N(R5)(R6), halide, CN, NO2, C(O)OR5, CON(R5)(R6), S(O)NR6 2, SO3H, SO2CH3, phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R5 and R6 are independently selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, and (C3-C6)cycloalkylhalo(C1-C6)alkyl groups; wherein R1 can occupy 0-2 positions in the ring of its occurrence; and wherein, in the event any two adjacent groups selected are OR5 groups, the two OR5 groups may optionally be cross-linked via their R5 functionalities to form an additional ring;
  • R2 is aryl, heteroaryl or heterocycyl, each of which is optionally substituted with up to 3 groups independently selected from R7;
  • R7 is selected from the group consisting of oxo, halo, cyano, nitro, amino, hydroxy, carboxy, (C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, (C1-C6)alkylheteroaryl, halo(C1-C6)alkylheteroaryl, hydroxy(C1-C6)alkylheteroaryl, (C3-C6)cycloalkylheteroaryl, halo(C3-C6)cycloalkylheteroaryl, hydroxy(C3-C6)cycloalkylheteroaryl, heterocyclylheteroaryl, (C1-C6)alkyl heterocyclylheteroaryl, halo(C1-C6)alkyl heterocyclylheteroaryl, hydroxy(C1-C6)alkyl heterocyclylheteroaryl, heteroalkyl, heterocyclylalkyl, (CH2)1-3COOH, (C1-C3)alkylcarbonyloxy, (C3-C6)cycloalkyl(C1-C6)alkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, (C1-C6)alkoxy, (C3-C6)cycloalkoxy, (C3-C6)cycloalkyl(C1-C6)alkoxy, halo(C1-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C3-C6)cycloalkyl(C1-C6)alkoxy, (C1-C6)alkylthio, (C3-C6)cycloalkythio, (C3-C6)cycloalkyl(C1-C6)alkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C3-C6)cycloalkyl(C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C3-C6)cycloalkylsulfinyl, (C3-C6)cycloalkyl(C1-C6)alkylsulfinyl, halo(C1-C6)alkylsulfinyl, halo(C3-C6)cycloalkylsulfinyl, halo(C3-C6)cycloalkyl(C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C3-C6)cycloalkylsulfonyl, (C3-C6)cycloalkyl(C1-C6)alkylsulfonyl, halo(C1-C6)alkylsulfonyl, halo(C3-C6)cycloalkylsulfonyl, halo(C3-C6)cycloalkyl(C1-C6)alkylsulfonyl, (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl, and (C1-C3)alkoxy(C1-C3)alkylaminocarbonyl;
  • R3 is selected from the group consisting of hydrogen, (C1-C3)alkyl, halo(C1-C3)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, and R8C═O, wherein R8 is selected from (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, aryl, and haloaryl groups; and
  • R4 is selected from the group consisting of (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, and hydroxy(C2-C6)alkenyl.
  • In one embodiment of the method requiring the compound having formula (V), R1 is hydrogen. In one embodiment, R2 is aryl. In one embodiment, R2 is heteroaryl. In one embodiment, R4 is (C1-C6)alkyl. In one embodiment, R3 is hydrogen. In one embodiment, the compound is
  • Figure US20210154213A1-20210527-C00016
  • In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula (VI)
  • Figure US20210154213A1-20210527-C00017
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
  • X is H or OR1;
  • R1 is independently selected from the group consisting of hydrogen, (C1-C3)alkyl, halo(C1-C3)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, and R3C═O, wherein R3 is selected from (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, aryl, and haloaryl groups; and
  • R2 is independently selected from hydrogen, R4, OR4, N(R4)(R5), halide, CN, NO2, C(O)OR4, CON(R4)(R4), S(O)NR42, SO3H, SO2CH3, phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R4 and R5 are independently selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, and (C3-C6)cycloalkylhalo(C1-C6)alkyl groups; wherein R2 can occupy 0-2 positions in the ring of its occurrence.
  • In one embodiment of the method requiring the compound having formula (VI), in the unfused benzene ring, X is a hydrogen. In one embodiment, in the unfused benzene ring, X is a hydroxyl. In one embodiment, R1 is hydrogen. In one embodiment, R2 is hydrogen. In one embodiment, the compound is one of
  • Figure US20210154213A1-20210527-C00018
  • In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula (VIII)
  • Figure US20210154213A1-20210527-C00019
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
  • R1 is selected from hydrogen, halogen, hydroxyl, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C2-C6)alkenyl, and halo(C2-C6)alkenyl;
  • R2 is selected from hydrogen, R3, OR3, N(R3)(R4), halide, CN, NO2, C(O)OR3, CON(R3)(R4), S(O)NR32, SO3H, SO2CH3, phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R3 and R4 are independently selected from hydrogen atom, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, and (C3-C6)cycloalkylhalo(C1-C6)alkyl groups; wherein R2 can occupy 0-2 positions in the ring; and wherein, in the event any two adjacent groups selected are OR3 groups, the two OR3 groups may optionally be cross-linked via their R3 functionalities to form an additional ring; and
  • n is an integer between 0 and 4.
  • In one embodiment of the method requiring the compound having formula (VIII), R1 is a halogen atom. In one embodiment, R1 is a (C2-C6)alkenyl. In one embodiment, R2 is a halogen atom. In one embodiment, each of R1 and R2 is a halogen atom. In one embodiment, the compound is one of
  • Figure US20210154213A1-20210527-C00020
  • In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula (IX)
  • Figure US20210154213A1-20210527-C00021
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
  • R1 is selected from the group consisting of hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, and hydroxy(C2-C6)alkenyl;
  • X is a hydrogen, halogen, hydroxy or, (C1-C6)alkyl; and
  • R2 is selected from hydrogen, R3, OR4, N(R3)(R4), halide, CN, NO2, C(O)OR3, CON(R3)(R4), S(O)NR3 2, SO3H, SO2CH3, phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R3 and R4 are independently selected from hydrogen atom, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, and (C3-C6)cycloalkylhalo(C1-C6)alkyl groups; wherein R2 can occupy 0-2 positions in the ring of its occurrence; and wherein, in the event any two adjacent groups selected are OR3 groups, the two OR3 groups may optionally be cross-linked via their R3 functionalities to form an additional ring.
  • In one embodiment of the method requiring the compound having formula (IX), X is a halogen. In one embodiment, R1 is an alkyl. In one embodiment, R2 is hydrogen. In one embodiment, the compound is
  • Figure US20210154213A1-20210527-C00022
  • In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula (X)
  • Figure US20210154213A1-20210527-C00023
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein,
  • X is O, S, or N;
  • each of n and p is an integer between 1 and 3;
  • R1 is aryl, heteroaryl, cyclyl, or heterocycyl, each of which is optionally substituted with up to 3 groups independently selected from R3;
  • R2 is selected from a group consisting of hydrogen R4, OR4, N(R4)(R5), halide, CN, NO2, C(O)OR4, CON(R4)(R5), S(O)NR42, SO3H, SO2CH3, phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R4 and R5 are independently selected from a group consisting of hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, and (C3-C6)cycloalkylhalo(C1-C6)alkyl groups; wherein R2 can occupy 0-2 positions in the ring; and wherein, in the event any two adjacent groups selected are OR4 groups, the two OR4 groups may optionally be cross-linked via their R4 functionalities to form an additional ring; and
  • R3 is selected from the group consisting of (C1-C3)alkyl, halo(C1-C3)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, and R6C═O, wherein R6 is selected from the (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, aryl, and haloaryl.
  • In one embodiment of the method requiring the compound having formula (X), X is an oxygen atom. In one embodiment, X is an oxygen atom and each of n and p is 1. In one embodiment, R1 is an aryl. In one embodiment, R is hydrogen. In one embodiment, the compound is
  • Figure US20210154213A1-20210527-C00024
  • In another aspect, provided herein is a method for treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula (XI)
  • Figure US20210154213A1-20210527-C00025
  • or a solvate or a pharmaceutically acceptable salt thereof
  • wherein
  • R1 is selected from the group consisting of hydrogen (C1-C3)alkyl, halo(C1-C3)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, and R3C═O, wherein R3 is selected from the (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, aryl, and haloaryl;
  • X is a hydrogen, halogen, hydroxy or, (C1-C6)alkyl; and
  • R2 is selected from the group consisting of hydrogen, R4, OR4, N(R4)(R5), halide, CN, NO2, C(O)OR4, CON(R4)(R5), S(O)NR42, SO3H, SO2CH3, phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R4 and R5 are independently selected from hydrogen atom, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, and (C3-C6)cycloalkylhalo(C1-C6)alkyl groups; wherein R2 can occupy 0-2 positions in the ring; and wherein, in the event any two adjacent groups selected are OR4 groups, the two OR4 groups may optionally be cross-linked via their R4 functionalities to form an additional ring.
  • In one embodiment of the method requiring the compound having formula (XI), R1 is a (C1-C3)alkyl. In one embodiment, R2 is hydrogen. In one embodiment, X is a halogen. In one embodiment, the compound is
  • Figure US20210154213A1-20210527-C00026
  • In another aspect, provided herein is a method of treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula (XVII) or (XVIII)
  • Figure US20210154213A1-20210527-C00027
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
    • R is
  • Figure US20210154213A1-20210527-C00028
    • or OH; R1 is
  • Figure US20210154213A1-20210527-C00029
    • or SO3H
  • R2 is H, X—R, CH3, lower alkyl, OCH3, OH, F, Cl, Br, NR, —CN, CO2R, CH2OH, or CF3.
    • R is OH,
  • Figure US20210154213A1-20210527-C00030
  • and
    X is NH, O, S, SO2, or N(C1-C6)alkyl.
  • In one embodiment of the method requiring the compound having formula (XVII) or (XVIII), the compound is
  • Figure US20210154213A1-20210527-C00031
  • In another aspect, provided herein is a method of treating presbyopia or cataract in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula (XII)
  • Figure US20210154213A1-20210527-C00032
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
  • R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C3)alkyl; halo(C1-C3)alkyl; (C3-C7)cycloalkyl; halo(C3-C7)cycloalkyl; and phenyl(C1-C3)alkyl, aminopheny(C1-C3)alkyl, and indanyl, wherein the phenyl or indanyl is optionally substituted with a halogen and the amino is optionally substituted with one or two (C1-C3)alkyl;
  • R3 is selected from the group consisting of hydrogen, (C3-C10)cycloalkyl; halo(C3-C10)cycloalkyl; (C3-C10)cycloalkyl(C1-C6)alkyl; halo(C3-C10)cycloalkyl(C1-C6)alkyl; (C1-C20)alkyl; halo(C1-C20)alkyl; aryl; haloaryl; aryl(C1-C6)alkyl; haloaryl(C1-C6)alkyl; and (C3-C10)heterocyclyl and halo(C3-C10)heterocyclyl, each optionally substituted at the heteroatom with R7CO, wherein R7 is selected from the group consisting of (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C10)cycloalkyl, halo(C3-C10)cycloalkyl, aryl, haloaryl, aryl(C1-C6)alkyl, haloaryl(C1-C6)alkyl, (C1-C6)alkylaryl, and halo(C1-C6)alkylaryl; and
  • R4, at each position where it occurs, is independently selected from the group consisting of hydrogen; halogen; (C1-C3)alkyl; halo(C1-C3)alkyl; (C1-C3)alkoxy; halo(C1-C3)alkoxy; OH, thiol, amino, and nitro.
  • In one embodiment of the method requiring the compound having formula (XII), R4 is hydrogen and each of R1 and R2 is a methyl group or a hydrogen. In a related embodiment, R4 is hydrogen and R3 is a six-member nitrogen containing a heterocyclyl group. Further, the nitrogen can be substituted with a phenylcarbonyl or benzylcarbonyl group, and the phenyl group can be optionally substituted with one or more fluorine atoms.
  • In one embodiment, R4 is hydrogen and R3 is a (C3-C10)cycloalkyl or a (C3-C10)cycloalkyl(C1-C3)alkyl group. In a related embodiment, either R1 or R2 or both are hydrogen.
  • In one embodiment, the compound is selected from the group consisting of
  • Figure US20210154213A1-20210527-C00033
    Figure US20210154213A1-20210527-C00034
  • In another aspect, provided herein is a method of treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having the formula (XIII)
  • Figure US20210154213A1-20210527-C00035
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
  • R1, at each position it occurs, is independently hydrogen or OR2, wherein R2 is selected from the group consisting of hydrogen, (C1-C3)alkyl; halo(C1-C3)alkyl; (C3-C7)cycloalkyl; halo(C3-C7)cycloalkyl; phenyl(C1-C3)alkyl, aminophenyl(C1-C3)alkyl, and indanyl, wherein the phenyl or indanyl is optionally substituted with a halogen and the amino is optionally substituted with one or two (C1-C3)alkyl;
  • R3 is selected from the group consisting of hydrogen, (C1-C3)alkyl; halo(C1-C3)alkyl; (C3-C7)cycloalkyl; halo(C3-C7)cycloalkyl; phenyl(C1-C3)alkyl, aminophenyl(C1-C3)alkyl, and indanyl, wherein the phenyl or indanyl is optionally substituted with a halogen and the amino is optionally substituted with one or two (C1-C3)alkyl;
  • R4, at each position it occurs, is independently selected from the group consisting of hydrogen; halogen; (C1-C3)alkyl; halo(C1-C3)alkyl; (C1-C3)alkoxy; halo(C1-C3)alkoxy; OH, thiol, amino, and nitro;
  • n is an integer between 0 and 5; and
  • m is an integer between 0 and 3.
  • In one embodiment of the method requiring the compound having formula (XIII), one or both of R2 and R3 are methyl groups and n is 2 or 3. In a related embodiment, R4 is hydrogen.
  • In one embodiment, the compound is selected from the group consisting of
  • Figure US20210154213A1-20210527-C00036
  • In another aspect, provided herein is a method of treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having the formula (XIV)
  • Figure US20210154213A1-20210527-C00037
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
  • R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C3)alkyl; halo(C1-C3)alkyl; (C3-C7)cycloalkyl; halo(C3-C7)cycloalkyl; phenyl(C1-C3)alkyl, aminophenyl(C1-C3)alkyl, and indanyl, wherein the phenyl or indanyl is optionally substituted with a halogen and the amino is optionally substituted with one or two (C1-C3)alkyl; and R3CO, wherein R3 is selected from the group consisting of hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C10)cycloalkyl, and halo(C3-C10)cycloalkyl;
  • R4, at each position that it occurs, is independently be selected from the group consisting of hydrogen; halogen; (C1-C3)alkyl; halo(C1-C3)alkyl; (C1-C3)alkoxy; halo(C1-C3)alkoxy; OH, thiol, amino, and nitro; and
  • R5 is selected from the group consisting of hydrogen, (C3-C10)cycloalkyl; halo(C3-C10)cycloalkyl; (C3-C10)cycloalkyl(C1-C6)alkyl; halo(C3-C10)cycloalkyl(C1-C6)alkyl; (C1-C20)alkyl; halo(C1-C20)alkyl; (C3-C10)heterocyclyl and halo(C3-C10)heterocyclyl, each optionally substituted at the heteroatom with R6CO, wherein R6 is selected from the group consisting of (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C10)cycloalkyl, halo(C3-C10)cycloalkyl, aryl, haloaryl, aryl(C1-C6)alkyl, haloaryl(C1-C6)alkyl, (C1-C6)alkylaryl, and halo(C1-C6)alkylaryl.
  • In one embodiment of the method requiring the compound having formula (XIV), each of R1 and R2 is a hydrogen, methyl or a CH3CO group and R4 is hydrogen. In a related embodiment, each of R1 and R2 is a CH3CO group. In another related embodiment, each of R1 and R2 is a CH3 group. In another related embodiment, each of R1 and R2 is a hydrogen. In another related embodiment, R5 is a hydrogen or a carboxyl group.
  • In one embodiment, the compound is selected from the group consisting of
  • Figure US20210154213A1-20210527-C00038
  • In another aspect, provided herein is a method of treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having the formula (XV)
  • Figure US20210154213A1-20210527-C00039
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
  • R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C3)alkyl; halo(C1-C3)alkyl; (C3-C7)cycloalkyl; halo(C3-C7)cycloalkyl; phenyl(C1-C3)alkyl, aminophenyl(C1-C3)alkyl, and indanyl, wherein the phenyl or indanyl is optionally substituted with a halogen and the amino is optionally substituted with one or two (C1-C3)alkyl;
  • R3, at each position it occurs, is independently selected from the group consisting of hydrogen; halogen; (C1-C3)alkyl; halo(C1-C3)alkyl; (C1-C3)alkoxy; halo(C1-C3)alkoxy; OH, thiol, amino, and nitro;
  • R4 is selected from the group consisting of (C1-C3)alkyl, OH, NR5R6, wherein each of R5 and R6 is independently selected from the group consisting of (C1-C3)alkyl; halo(C1-C3)alkyl, (C3-C7)cycloalkyl; halo(C3-C7)cycloalkyl; and phenyl(C1-C3)alkyl, wherein the phenyl is optionally substituted with halogen, (C1-C3)alkyl, or hydroxyl;
  • X is hydrogen or nitro; and
  • Y is H or CN.
  • In one embodiment of the method requiring the compound having formula (XV), R1 and R2 are hydrogen. Further, X can be a nitro group. Further, Y can be a cyano group. Further, R4 can be NR5R6, R5 being hydrogen. Further, R4 can be an alkyl, a dialkylamine, or a hydroxyl.
  • In one embodiment, the compound is one of
  • Figure US20210154213A1-20210527-C00040
  • In another aspect, provided herein is a method of treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having the formula (XVI)
  • Figure US20210154213A1-20210527-C00041
  • or a solvate or a pharmaceutically acceptable salt thereof, wherein
  • R1 is hydrogen or OR3, wherein R3 is selected from the group consisting of hydrogen, (C1-C3)alkyl; halo(C1-C3)alkyl; (C3-C7)cycloalkyl; halo(C3-C7)cycloalkyl; phenyl(C1-C3)alkyl, aminophenyl(C1-C3)alkyl, and indanyl, wherein the phenyl or indanyl is optionally substituted with a halogen and the amino is optionally substituted with one or two (C1-C3)alkyl; and
  • R2, at each position it occurs, is independently selected from the group consisting of hydrogen; halogen; (C1-C3)alkyl; halo(C1-C3)alkyl; (C1-C3)alkoxy; halo(C1-C3)alkoxy; OH, sulfonyl, thiol, amino, and nitro.
  • In one embodiment of the method requiring the compound having formula (XVI), R1 is hydrogen. In one embodiment, R2 is hydrogen. In one embodiment, the compound is one of
  • Figure US20210154213A1-20210527-C00042
  • In another aspect, provided herein is a method of treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound selected from the group consisting of
  • Figure US20210154213A1-20210527-C00043
    Figure US20210154213A1-20210527-C00044
  • In another aspect, provided herein is a method of preventing and/or treating transthyretin (TTR)-associated amyloidosis in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula
  • Figure US20210154213A1-20210527-C00045
  • or a pharmaceutically acceptable salt thereof,
  • wherein R1 is selected from the group consisting of
  • Figure US20210154213A1-20210527-C00046
  • wherein R7 is (C1-C6)alkyl and R8 is (C1-C6)alkyl, aryl, or a polyethylene glycol group.
  • In one embodiment, the compound is
  • Figure US20210154213A1-20210527-C00047
  • In another aspect, provided herein is a method of treating Parkinson's disease in a subject in need thereof. The method comprises administering to the subject an effective amount of a composition comprising a compound having the formula
  • Figure US20210154213A1-20210527-C00048
  • wherein R1 is selected from the group consisting of
  • Figure US20210154213A1-20210527-C00049
  • wherein R7 is (C1-C6)alkyl and R8 is (C1-C6)alkyl, aryl, or a polyethylene glycol group.
  • In one embodiment, the compound is
  • Figure US20210154213A1-20210527-C00050
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIGS. 1A-1D show experimental results described in prior art. FIGS. 1A and 1B depict graphs for stiffness of lens cortex and nucleus (1A), and loss in accommodative power (diopters) (1B) as a function of age. Graphs represent a summary of four separate studies on human accommodation. FIG. 1C depicts mass distribution in the water-soluble fraction in young (19 years) (solid line and filled circle) and aged (83 years) (broken line and open circle) human lenses using SEC-MALS (multiangle light scattering). FIG. 1D shows changes in the content of soluble AC (open circle) and high molecular weight protein (closed circle) in the lens nucleus as a function of age.
  • FIG. 2A shows the effect of exposing hAAC at 500 ug/ml to UVC. FIG. 2B shows the effect of subjecting hAAC to Ca+2/heat for 0, 5, 15 and 30 mins. Absorbance at 360/400 nm was measured at each time point. Mean±SEM of the measurements are shown.
  • FIGS. 3A and 3B show representative data for extent to which hAAC is protected by compounds (or DMSO control) from becoming aggregated. Aggregation was monitored for 120 minutes by absorbance at 360 nm for UV induced aggregation (3A) or at 400 nm for heat induced aggregation (3B). Mean±SEM of the measurements are shown.
  • FIGS. 4A-4F show structure activity relationship (SAR) based classification of compounds discovered from UV and heat induced hAAC aggregation assays. Compounds are grouped into three series, Series-1: Macrocyclics; Series-2: “Covalent,” and Series-3: Catechols. FIGS. 4A, 4C, and 4E show EC50 curves for one compound, respectively, from the macrocyclic, covalent, and the catechol series. FIGS. 4B, 4D, and 4F show percent protection from aggregation at 200 μM of compounds, respectively, from the macrocyclic, covalent, and the catechol series. Measurements for assessing protection were performed in triplicate.
  • FIG. 5 shows results of a biochemical test for target (i.e., hACC) engagement by SMD. hACC (500 ug/ml) was treated overnight with 200 μM CAP1613 and CAP1614 and exposed to UV for 0, 5, 15 or 30. Samples from each time point were run on a SDS-PAGE under non-reducing condition. Insoluble and soluble HMW aggregates are shown by boxes at the top and bottom of the gel, respectively.
  • FIG. 6A shows sequence alignment of mammalian AACs. The conserved Cys (Cys131) is highlighted. Cys (Cys142), present only inhuman and chimpanzee, is also highlighted. A 3D model structure of hAAC (inset), showing the location of the residues Cys131 and Cys142, is shown to the right. FIG. 6B shows reaction scheme for modification of cysteine with cysteine-reactive acrylamides (a) and chloro-acetamides (b).
  • FIG. 7A shows results for viability of HLE cells (B3 and SRA 01/04) exposed to UV (left) or heat (right), assessed 24 hours post-exposure by. Alamar blue was used for assessing viability. Mean±SEM of the measurements are shown.
  • FIG. 7B shows protection of SRA 01/04 cells (human lens epithelial cell line), pre-incubated with varying concentrations of compounds two hours prior to UV exposure. Relative protection was measured as percent viability compared to vehicle control 24 hours following UV exposure. Effect of compounds from each of three distinct chemical series (macrocyclics, covalent, and catechol) are shown. Mean±SEM of the measurements are shown.
  • FIG. 8A shows ectopic expression of AAC-EGFP in B-3 cells forms inclusions that co-localize with p62 (arrows). FIG. 8B shows results of automated image analysis of >2500 cells. A statistically significant increase in GFP-positive inclusions due to AAC overexpression was observed. Mean±SEM of the measurements and p value (t test) are shown.
  • FIGS. 9A-9F show EC50 curves of select compounds depicting the fold change in protection of hAAC against UVC and Ca+2 induced aggregation.
  • FIGS. 10A-10C are graphs showing dose-dependent protection of human lens epithelial cells (HLE) from UV-irradiation induced cell death. SRA 01/04 HLE cells were pre-incubated for 3 hours with varying concentrations of compounds and exposed to UV light (9600 mJ/cm2, 254 nm). Percent viability was assessed by Alamar blue compared to non-irradiated controls after 24 hours. Mean±SD and linear regression curve fit produced with Graphpad software, and calculated EC50s (μM) are provided.
  • FIGS. 11A-11D show the effect of CAP1159 on exposure of eye lens to UVC radiation.
  • FIG. 11A shows representative dark field digital images of porcine eye lens (from a set of n=12 lens experiment), when exposed to 2 hours of 480 mJ/cm2 per minute of UVC radiation in presence or absence of varying concentrations of CAP1159. The top row of the figure corresponds to lenses that were not exposed to UVC but contained same percent of DMSO as those that were exposed to UVC. The lenses were monitored and imaged for three days following the exposure to UVC. No drug was added to the lenses post UVC exposure.
  • FIG. 11B shows results of scoring of lenses (n=12) for cataract on days 1, 2, and 3 after exposure to UVC radiation in the study shown in FIG. 11 A. The scale (0-9) for grading is shown in FIG. 11A.
  • FIG. 11C shows progression of cataract following UVC exposure over a period of three days.
  • FIG. 11D is a bar graph showing soluble protein content from treatment (CAP1159) and control groups as measured at 280 nm at the end of the three-day period. Lenses from each group were lysed and the supernatant pooled to measure the total soluble protein content from each group.
  • FIGS. 12A-12D show the effect of CAP1160 on exposure of eye lens to UVC radiation.
  • FIG. 12A shows representative dark field digital images of porcine eye lens (from a set of n=12 lens experiment), when exposed to 2 hours of 480 mJ/cm2 per minute of UVC radiation in presence or absence of varying concentrations of CAP1160. The top row of the figure corresponds to lenses that were not exposed to UVC but contained same percent of DMSO as those that were exposed to UVC. The lenses were monitored and imaged for three days following the exposure to UVC. No drug was added to the lenses post UVC exposure.
  • FIG. 12B. shows results of scoring of lenses (n=12) for cataract on days 1, 2, and 3 after exposure to UVC radiation in the study shown in FIG. 12A. The scale (0-9) for grading is shown in FIG. 12A
  • FIG. 12C progression of cataracts following post UVC exposure as monitored over a period of three days.
  • FIG. 12D is a bar graph showing soluble protein content from treatment (CAP1160) and control groups as measured at 280 nm at the end of the three-day period. Lenses from each group were lysed and the supernatant pooled to measure the total soluble protein content from each group.
    •  DETAILED DESCRIPTION Compounds and Definitions
  • The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), and iodine (iodo, —I).
  • The term “alkyl”, used alone or as a part of a larger moiety such as e.g., “haloalkyl”, means a saturated monovalent straight or branched hydrocarbon radical having, unless otherwise specified, 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like. “Monovalent” means attached to the rest of the molecule at one point.
  • The terms “cycloalkyl” used alone or as part of a larger moiety, refers to a saturated cyclic aliphatic monocyclic, bicyclic or tricyclic ring system, as described herein, having from, unless otherwise specified, 3 to 10 carbon ring atoms. Monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Bicyclic cycloalkyl groups include e.g., cycloalkyl group fused to another cycloalkyl group, such as decalin or a cycloalkyl group fused to an aryl group (e.g., phenyl) or heteroaryl group, such as tetrahydronaphthalenyl, indanyl, 5,6,7,8-tetrahydroquinoline, and 5,6,7,8-tetrahydroisoquinoline. An example of a tricyclic ring system is adamantane. It will be understood that the point of attachment for bicyclic cycloalkyl groups can be either on the cycloalkyl portion or on the aryl group (e.g., phenyl) or heteroaryl group that results in a stable structure. It will be further understood that when specified, optional substituents on a cycloalkyl may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl is attached.
  • The term “heterocyclyl” means a 4-, 5-, 6- and 7-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. The terms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclic moiety”, and “heterocyclic radical”, may be used interchangeably. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxetanyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and tetrahydropyrimidinyl. A heterocyclyl group may be mono- or bicyclic. Unless otherwise specified, bicyclic heterocyclyl groups include, e.g., unsaturated or saturated heterocyclic radicals fused to another unsaturated heterocyclic radical or aromatic or heteroaryl ring, such as for example, chromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, tetrahydronaphthyridinyl, indolinonyl, dihydropyrrolotriazolyl, imidazopynmidinyl, quinolinonyl, dioxaspirodecanyl. It will be understood that the point of attachment for bicyclic heterocyclyl groups can be on the heterocyclyl group or aromatic ring that results in a stable structure. It will also be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached.
  • The term “heteroaryl” used alone or as part of a larger moiety as in “heteroarylalkyl”, “heteroarylalkoxy”, or “heteroarylaminoalkyl”, refers to a 5-10-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S and includes, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, and quinoxalinyl. A heteroaryl group may be mono- or bicyclic. It will be understood that when specified, optional substituents on a heteroaryl group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached. As used herein, the term “aryl”, used alone or in conjunction with other terms, refers to a 6-14 membered aromatic ring containing only ring carbon atoms. The aryl ring may be monocyclic, bicyclic or tricyclic. Non-limiting examples include phenyl, naphthyl or anthracenyl, and the like. It will also be understood that when specified, optional substituents on an aryl group may be present on any substitutable position. In an embodiment, the aryl group is unsubstituted or mono- or di-substituted.
  • As used herein the terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.
  • The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts.
  • Pharmaceutically acceptable basic/cationic salts include, the sodium, potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.
  • Pharmaceutically acceptable acidic/anionic salts include, e.g., the acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, carbonate, citrate, dihydrochloride, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, malate, maleate, malonate, mesylate, nitrate, salicylate, stearate, succinate, sulfate, tartrate, and tosylate.
    • Route of Delivery
  • Methods used to deliver compounds described herein to the eye include topical, subconjunctival, intravitreal, and systemic.
  • Topical: Topical ocular drug administration is typically accomplished by eye drops. Contact time on the eye surface is short, but can be prolonged using specific formulations, e.g., gels, gelifying formulations, ointments, and inserts. Typically, the basic nature of the solution containing the drug composition is aqueous and as such, agents designed to increase the viscosity of the solution may be employed. Such agents include, for example, hydroxypropyl methylcellulose, carbopol, polyvinyl alcohol, and the like.
  • Subconjunctival administration: Traditionally subconjunctival injections have been used to deliver drugs at increased levels to the uvea. This mode of administration can be used to deliver drugs in controlled release formulations to the posterior segment and to guide the healing process after surgery.
  • Intravitreal administration: Direct drug administration into the vitreous offers the advantage of more straightforward access to the vitreous and retina. Delivery from the vitreous to the choroid is more complicated, however, due to the hindrance by the RPE (Retinal Pigment Epithelium) barrier. Small molecules are able to diffuse rapidly in the vitreous but the mobility of large molecules, particularly positively charged, is restricted. An injectable composition suitable for intraocular injection typically comprises a solution of the drug or a fine particle suspension, which may enable sustained delivery to the eye. Formulations are usually aqueous and may commonly include solubilization enhancers such as, but not limited to, polyvinyl alcohol, Tween 80, solutol, cremophore, and cyclodextrin. These solubilization enhancers may be used in combination. The formulation is typically in the pH range of 3-8, which is be regarded as acceptable for intravitreal formulations. To achieve an acceptable pH, buffering systems are sometimes used. These include but are not limited to citrate and phosphate based buffering systems. The tonicity of the intravitreal formulation may be adjusted to remain within a desirable range which typically would be 250-360 mOsm/kg. Adjustment of tonicity may be achieved for example by addition of sodium chloride. Typically, intravitreal formulations are produced by sterile manufacture for single use. Preserved formulations can be used, for example formulations containing a preservative such as benzoyl alcohol. The dose of the active agent in the compositions of the invention will depend on the nature and degree of the condition, the age and condition of the patient and other factors known to those skilled in the art. Administration can be either as a single injection with no further dosing or multiple injections.
  • Systemic: Systemic medication is required for posterior segment therapy and to complement topical therapy for the anterior segment. The posterior segment always requires systemic therapy, because most topical medications do not penetrate to the posterior segment. Retrobulbar and orbital tissues are treated systemically.
    • Prodrug Formulations and Permeability Enhancers
  • In some embodiments, the present technology provides a method of treating presbyopia or cataract, the method requiring administration of an effective amount of a composition comprising a compound described herein, the compound being present in a prodrug form, or being converted to a prodrug form. Prodrug formulations use pharmacologically inactive derivatives of drug molecules that are better able to penetrate the cornea (e.g., they are more lipophilic) than the standard formulation of the drug. See review by Brian G. Short, Toxicologic Pathology, 36:49-62, 2008. As described in the review and the references cited therein, within the cornea or after corneal penetration, the prodrug is either chemically or enzymatically metabolized to the active parent compound. Enzyme systems identified in ocular tissues include esterases, ketone reductase, and steroid 6β-hydroxylase.
  • Most prodrugs are delivered conventionally by topical application such as antiviral prodrugs ganciclovir and acyclovir, although ganciclovir has also been delivered intravitreally by injection or as a nonbiodegradable reservoir (see below). Delivery of a drug with a nonnatural enzyme system in the cornea has been achieved with topical 5-flurocytosine, a prodrug of 5-fluorouracil, administered after subconjunctival transplantation of cells containing the converting enzyme cytosine deaminase. Increased corneal penetration into the anterior segments can be achieved with the addition of permeability enhancers to the drug formulation. Surfactants, bile acids, chelating agents, and preservatives have all been used. Cyclodextrins, cylindrical oligonucleotides with a hydrophilic outer surface and a lipophilic inner surface that form complexes with lipophilic drugs, are among the more popular permeability enhancers. They increase chemical stability and bioavailability and decrease local irritation, and they have been used with corticosteroids, choloramphenicol, diclofenac, cyclosporine, and sulfonamide carbonic anhydrase inhibitors. The present invention includes small molecule disaggregases (SMDs) that are synthesized as prodrugs such that they have a better ability to permeate the cornea.
    • EXAMPLES Example 1: Recombinant hAAC Forms HMW Aggregates Upon Exposure of UV and Heat
  • The factors that contribute to the age-related loss of soluble functional AAC includes post translational modification of amino-acid residues due to exposure to UV and heat. Therefore, to identity potent SMDs, experimental conditions were developed under which hAAC, when exposed to UV-C radiation or heated to 50° C., formed HMW aggregates (FIGS. 2A-2D). Consistent with published reports, hAAC HMW aggregates formed under UV-C radiation remain insoluble compared to the heat induced HMW (FIGS. 2C & 2D). The system described herein recapitulates the factors that contribute to formation of presbyopia.
    • Example 2: Identification of Small Molecule Disaggregases (SMD) of hAAC
  • A large number of small molecule compounds were screened for their ability to protect hAAC from forming HMW aggregates. In the screen based on UV-induced aggregation, 310 compounds were tested, whereas in that based on Ca2+/heat-induced aggregation, 206 compounds were tested. Each compound was used at 200 uM concentration. In view of the fact that nearly 40% of eye lens consists of AC, a high concentration of recombinant hAAC (500 ug/ml for UV and 400 μg/ml for heat) was used in the screens. The screening resulted in the identification of a number of compounds that showed efficacy in protecting hAAC from forming HWM aggregates (Table 1). These compounds are referred to as SMDs. A representative set of data is presented in FIGS. 3A-3B. Details of the procedure for the identification of SMDs is described in the following.
  • For identifying compounds that are effective in preventing the aggregation of human AAC in eye lens and can function as or developed into pharmacological agents for the treatment of presbyopia, it is important that the biochemical screening method (i) be based on non-enzymatic conditions that contribute to the loss of function of AAC and formation of HMW aggregates, and (ii) uses relevant species of AAC, particularly since human AAC contains a unique cysteine residue (Cys142). Accordingly, the screening method employed here has taken these factors into consideration.
  • Library design: Since the SMDs of the present disclosure are meant for ophthalmic application, factors that are key are those that play a role trans-cellular drug permeation. These factors are log P, pKa, and MW. Log P is the most important feature of the drug since it determines whether the SMD can cross the epithelium layer. A Log P of 2-3 provides optimal chemical composition for absorption across the corneal layer. The SMDs must also possess adequate aqueous solubility since it must diffuse across the water-filled stroma, and it is the initial drug concentration in the tear film that determines the driving force for corneal penetration. Accordingly, the library of compounds used for screening for SMDs was assembled such that the compounds included possessed physicochemical properties of drugs known to have high tissue penetration. See Table 1 below for details.
  • TABLE 1
    Physicochemical property criteria for library design
    Property Criteria
    Mol. Wt. (Da) ≤650
    cLogP 1-4
    H-bond acceptor ≤6
    H-bond donor ≤5
    No. of rotatable bonds ≤6
    Polar surface area (PSA) (Å2) ≤70
    Aqueous Solubility (ug/ml) 500
  • To perform screening, each compound at 200 μM concentration (0.5% DMSO) was incubated with hAAC (500 ug/ml for UV and 400 ug/ml for heat induced aggregation) for 30 mins at room temperature and absorbance measured at multiple time points (0, 30, 60, 90 and 120 minutes). Compounds showing greater than 50% protection relative to untreated were retested and rank ordered to provide dose dependent EC50 value measurements. Table 2 below shows distribution of compounds and the extent to which they protect hAAC from aggregating.
  • Structural analysis of the SMDs identified revealed that compounds that protect against aggregation of hAAC under UV exposure can be grouped into two classes, namely macrocyclics and “covalent”, and those that protect against heat induced aggregation as catechols. The molecular structures of the hits for each series, along with their percent protection, are shown in FIGS. 4A-4F. Dose-dependent potency curve and EC50 value for one compound from each series are also shown. The fact that the SMDs identified prevent the aggregation of hAAC when exposed to UV, demonstrate their ability to directly engage hAAC.
  • TABLE 2
    Distribution of compounds showing the
    protection of aggregation of hAAC
    No. of compounds
    % protection UV Heat (50° C.)
    ≤0 225 170
    ≤20 32 20
    ≤40 9 9
    ≤60 5 2
    ≤80 7 2
    ≤100 4 1
    >100 28 2
    • Example 3: SMDs Forming Covalent Bond with ACC Prevent HMW hAAC Aggregate Formation
  • AAC contains two cysteine residues which are known to undergo post translational modification to form intra/intermolecular disulfide bonds resulting in HMW aggregates. As such, it was hypothesized that the formation of disulfide bonds could be prevented using a structure-guided design employing covalent bond forming cysteine-reactive drug-like compounds targeting the two cysteines in order to develop potent and selective SMDs of hAAC. Accordingly, irreversible electrophile cysteine-reactive compounds comprising acrylamides and chloro-acetamides functional groups were included in screening assays for SMDs. These compounds were made using the synthesis route shown below in Scheme 1.
  • Figure US20210154213A1-20210527-C00051
  • The screening resulted in the identification of multiple compounds (FIGS. 4C-4D). These compounds are referred to as “covalent” given their potential to from covalent bond with the cysteine residue (FIGS. 6A and 6B).
    • Example 4: Cell Based Assays Using Human Lens Epithelial (HLE) Cells
  • Cell-based using assays using human lens epithelial cell lines SRA 01/04 and B3 were also performed. The cells were exposed to UV or heat and cell viability assessed 24 hours post-exposure by Alamar blue staining. The results are shown in FIGS. 7A and 7B. In another experiment, SRA 01/04 cells were pre-incubated with varying concentrations of compounds two hours prior to UV exposure. Relative protection was measured as percent viability compared to vehicle control 24 hours following UV exposure. Effect of compounds from each of three distinct chemical series (macrocyclics, covalent, and catechol) are shown in FIG. 7B. Mean±SEM of the measurements are shown.
  • Ectopic expression of AAC-EGFP in B-3 cells shows that AAC forms inclusions that co-localize with p62 (arrows) (FIG. 8A). Automated image analysis of >2500 cells is shown in FIG. 8B. A statistically significant increase in GFP-positive inclusions due to AAC overexpression was observed. Mean±SEM of the measurements and p value (t test) are shown. The results show that high-content screening could be used to evaluate the cellular pharmacodynamic effects of SMDs for measuring cellular aggregates of AAC.
    • Example 5. Synthesis of Catechol Derivatives
  • Catechol derivatives described herein can be synthesized using the reaction schemes shown below. Specific examples of the derivatives synthesized are described following the reaction schemes.
  • Figure US20210154213A1-20210527-C00052
  • Reagents and conditions for scheme 1: (a) Grignard Reaction conditions, Diethylether, 0° C. to r.t.; (b)oxidation, PCC, CH2Cl2, r.t., (c) Pd/C, H2, methanol, r.t.; (d) 70% HNO3, r.t.; (e) BBr3, CH2Cl2, r.t.; (f) PEG-acid, EDC, DMAP, r.t. In this reaction scheme, many different substituents can be used as the different R groups. R6, R7, R8, R9, and R10 can independently be, for example, H, alkyl, aryl, halogen, nitro, amino, trifluoromethyl, and trifluoromethoxy.
  • Figure US20210154213A1-20210527-C00053
  • Reagents and conditions for scheme 2: (g), EDC, HOBt, DIEA, DMF, rt, 16 h. In this reaction scheme, many different substituents can be used as the different R groups. R17, R18, and R19 can independently be, for example, H, alkyl, aryl, halogen, nitro, amino, methoxy, trifluoromethyl and trifluoromethoxy. R20 can be an alkyl or an aryl group.
  • Figure US20210154213A1-20210527-C00054
  • Reagents and conditions for scheme 3: (h) EDC, HOBt, DIEA, DMF, rt, 16 h; (i) TFA, CH2Cl2, rt, 6 h; (j), Aryl amines, EDC, HOBt, DIEA, DMF, rt, 20 h. In this reaction scheme, many different substituents can be used as the different R groups. R17, R18, R19, R21, R22, R23, R24, and R25 can, for example, independently be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, and trifluoromethyl.
  • Figure US20210154213A1-20210527-C00055
  • Scheme 4: Reagents and conditions for scheme 4: (k) EDC, HOBt, DIEA, DMF, rt, 15 h; (1) TFA, CH2Cl2, rt, 6 h; (m) R26—CO2H, EDC, HOBt, DIEA, DMF, rt, 22 h. In this reaction scheme, many different substituents can be used as the different R groups. R17, R18, and R19 can, for example, independently be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, and trifluoromethyl. R26 can be an alkyl or an aryl group.
    • Synthesis of N-[2-(3,4-dimethoxyphenyl)ethyl]cyclobutanecarboxamide (CAP1226)
  • CAP1226 was synthesized using the appropriate reagents and starting materials as shown in Scheme 2 above. Briefly, a mixture of 3,4-dimethoxyphenethylamine (1 mmol), cyclobutanecarboxylic acid (1 mmol), EDC (1.2 mmol), HOBt (1.2 mmol), and DIEA (1.5 mmol) in DMF (3 mL) were stirred for 16 h at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate solution, water, and brine respectively. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed over silica gel using ethyl acetate hexane solvent system to afford the pure product CAP1226 as a solid (82%). The compound was characterized by NMR and Mass spectroscopy. 1H NMR (500 MHz, DMSO-d6) δ 1.92-2.05 (m, 4H), 2.44-2.46 (m, 2H), 2.91-3.15 (m, 3H), 6.68 (dd, J=8 and 2 Hz, 1H), 6.73 (d, J=1.7 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 7.56 (t, J=5.4 Hz, 1H, NH); ESI-MS m/z 264 (M+H)+. Other compounds were selected using schemes 2, 3, or 4.
    • N,N-bis[2-(3,4-dimethoxyphenyl)ethyl]hexanediamine (CAP1225)
  • CAP1225 was prepared using scheme 2 shown above. The compound was characterized by NMR and Mass spectroscopy.
  • 1H NMR (500 MHz, DMSO-d6) δ 1.45-1.48 (m, 4H), 1.98-2.01 (m, 4H), 2.56-2.57 (m, 4H), 3.01-3.09 (m, 4H), 3.76 (s, 6H), 3.79 (s, 6H), 6.67 (d, J=7.2 Hz, 1H), 6.69 (d, J=7.2 Hz, 2H), 6.75 (d, J=7.5 Hz, 2H), 6.79 (d, J=1.2 Hz, 2H), 6.81 (d, J=1.2 Hz, 2H), 7.72 (t, J=5.4 Hz, 2H, NH); ESI-MS m/z 474 (M+H)+.
    • N-[2-(3,4-dimethoxyphenyl)ethyl]-1(phenylacetyl)-4-piperidinecarboxamide (CAP1227)
  • CAP1227 was prepared using scheme 2 shown above. The compound was characterized by NMR and Mass spectroscopy.
  • 1H NMR (500 MHz, DMSO-d6) δ 1.41-1.52 (m, 4H), 2.32-2.38 (m, 1H), 2.61-2.68 (m, 3H), 2.88-2.92 (m, 1H), 3.21-3.29 (m, 2H), 3.62 (s, 2H), 3.72 (s, 3H), 3.75 (s, 3H), 3.92-3.95 (m, 1H), 4.41-4.45 (m, 1H), 6.61 (dd, J=7.8 and 1.7 Hz, 1H), 6.72 (d, J=1.7 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 7.19-7.25 (m, 3H), 7.28-7.32 (m, 2H), 7.68 (t, J=5.2 Hz, 1H, NH); ESI-MS m/z 412 (M+H)+.
    • N,N′-bis[2-(3,4-dimethoxyphenyl)ethyl]pentanediamide (CAP1228)
  • CAP1228 was prepared using scheme 3 shown above. The compound was characterized by NMR and Mass spectroscopy.
  • 1H NMR (500 MHz, DMSO-d6) δ 1.61-162 (m, 2H), 1.98-2.10 (m, 4H), 2.65-2.70 (m, 4H), 3.30-3.39 (m, 4H), 3.78 (s, 6H), 3.79 (s, 6H), 6.67 (dd, J=8 and 1.6 Hz, 2H), 6.77 (d, J=1.6 Hz, 2H), 6.82 (d, J=8 Hz, 2H), 7.71 (t, J=5.4 Hz, 2H, NH); ESI-MS m/z 460 (M+H)+.
    • N-[2-(3,4-dimethoxyphenyl)ethyl]cyclopropanecarboxamide (CAP1230)
  • CAP1230 was prepared using scheme 2 shown above. The compound was characterized by NMR and Mass spectroscopy.
  • 1H NMR (500 MHz, DMSO-d6) δ 0.58-0.67 (m, 4H), 1.46-1.53 (m, 1H), 2.62-2.68 (m, 2H), 3.21-3.27 (m, 2H), 3.76 (s, 3H), 3.77 (s, 3H), 6.67 (d, J=8 and 1.6 Hz, 1H), 6.75 (d, J=1.6 Hz, 1H), 6.81 (d, J=8 Hz, 1H), 7.98 (t, J=5.6 Hz. 1H, NH); ESI-MS m/z 250 (M+H)+.
    • N-[2-(3,4-dimethoxyphenyl)ethyl]cyclopentanecarboxamide (CAP1231)
  • CAP1231 was prepared using scheme 2 shown above. The compound was characterized by NMR and Mass spectroscopy.
  • 1H NMR (500 MHz, DMSO-d6) δ 1.48-1.78 (m, 5H), 2.58-2.61 (m, 4H), 3.27-3.35 (m, 4H), 3.75 (s, 3H), 3.76 (s, 3H), 6.72 (dd, J=7.8 and 1.6 Hz, 1H), 6.79 (d, J=1.6 Hz, 1H), 6.84 (d, J=8 Hz, 1H), 7.77 (t, J=5.4 Hz, 1H, NH); ESI-MS m/z 278 (M+H)+.
    • N-[2-(3,4-dimethoxyphenyl)ethyl]-1-(4-fluorophenyl)-4-piperidinecarboxamide (CAP1232)
  • CAP1232 was prepared using scheme 2 shown above. The compound was characterized by NMR and Mass spectroscopy.
  • 1H NMR (500 MHz, DMSO-d6) δ 1.47-1.71 (m, 4H), 2.37-2.41 (m, 1H), 2.62-2.71 (m, 3H), 2.80-2.88 (m, 2H), 3.23-3.32 (m, 3H), 3.75 (s, 3H), 3.76 (s, 3H), 6.65 (dd, J=8 and 1.6 Hz, 1H), 6.72 (d, J=1.6 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 7.16-7.22 (, 2H), 7.41-7.46 (m, 2H), 7.72 (t, J=5.2 Hz, 1H, NH); ESI-MS m/z 415 (M+H)+.
    • Example 6. Effectiveness of Select Catechol Derivatives in Preventing Ca+2 and UVC Induced Aggregation of Alpha-A Crystalline
  • Table 3 below lists select catechol derivatives and their effectiveness in preventing Ca+2 and UVC induced aggregation of alpha-A crystalline.
  • TABLE 3
    Percent
    protection
    Compound (at 200
    ID Molecular Structure μM)
    CAP1176
    Figure US20210154213A1-20210527-C00056
         		   76
    CP1192
    Figure US20210154213A1-20210527-C00057
    CP1194
    Figure US20210154213A1-20210527-C00058
         		   25
    CAP1042
    Figure US20210154213A1-20210527-C00059
         		   6
    CAP1043
    Figure US20210154213A1-20210527-C00060
         		 −5
    CAP1044
    Figure US20210154213A1-20210527-C00061
         		 −16
    CAP1045
    Figure US20210154213A1-20210527-C00062
    CAP1046
    Figure US20210154213A1-20210527-C00063
    CAP1047
    Figure US20210154213A1-20210527-C00064
         		 −17
    CAP1048
    Figure US20210154213A1-20210527-C00065
    CAP1049
    Figure US20210154213A1-20210527-C00066
         		 −5
    CAP1050
    Figure US20210154213A1-20210527-C00067
    CAP1051
    Figure US20210154213A1-20210527-C00068
         		 −28
    CAP1052
    Figure US20210154213A1-20210527-C00069
         		   3
    CAP1053
    Figure US20210154213A1-20210527-C00070
         		   52
    CAP1054
    Figure US20210154213A1-20210527-C00071
    CAP1055
    Figure US20210154213A1-20210527-C00072
         		   1
    CAP1056
    Figure US20210154213A1-20210527-C00073
         		 −5
    CAP1057
    Figure US20210154213A1-20210527-C00074
         		 −8
    CAP1058
    Figure US20210154213A1-20210527-C00075
         		 −27
    CAP1072
    Figure US20210154213A1-20210527-C00076
         		   53
    CAP1110
    Figure US20210154213A1-20210527-C00077
         		   19
    CAP1112
    Figure US20210154213A1-20210527-C00078
         		   12
    CAP1113
    Figure US20210154213A1-20210527-C00079
    CAP1159
    Figure US20210154213A1-20210527-C00080
         		   27
    CAP1160
    Figure US20210154213A1-20210527-C00081
         		   65
    CAP1215
    Figure US20210154213A1-20210527-C00082
         		 −47
    CAP1219
    Figure US20210154213A1-20210527-C00083
         		 −5
    CAP1220
    Figure US20210154213A1-20210527-C00084
         		   20
    CAP1221
    Figure US20210154213A1-20210527-C00085
    CAP1222
    Figure US20210154213A1-20210527-C00086
         		   38
    CAP1223
    Figure US20210154213A1-20210527-C00087
         		   29
    CAP1224
    Figure US20210154213A1-20210527-C00088
         		   46
    CAP1225
    Figure US20210154213A1-20210527-C00089
         		   50
    CAP1226
    Figure US20210154213A1-20210527-C00090
         		   72
    CAP1227
    Figure US20210154213A1-20210527-C00091
         		   46
    CAP1228
    Figure US20210154213A1-20210527-C00092
         		   60
    CAP1229
    Figure US20210154213A1-20210527-C00093
         		   22
    CAP1230
    Figure US20210154213A1-20210527-C00094
         		   18
    CAP1231
    Figure US20210154213A1-20210527-C00095
         		   51
    CAP1232
    Figure US20210154213A1-20210527-C00096
         		   41
    CAP1236
    Figure US20210154213A1-20210527-C00097
         		 −2
    CAP1237
    Figure US20210154213A1-20210527-C00098
    CAP1238
    Figure US20210154213A1-20210527-C00099
    CAP1239
    Figure US20210154213A1-20210527-C00100
         		   23
    CAP1240
    Figure US20210154213A1-20210527-C00101
         		 −13
    CAP1241
    Figure US20210154213A1-20210527-C00102
         		  135
    CAP1242
    Figure US20210154213A1-20210527-C00103
    CAP1264
    Figure US20210154213A1-20210527-C00104
         		   3
    CAP1265
    Figure US20210154213A1-20210527-C00105
         		 −6
    CAP1266
    Figure US20210154213A1-20210527-C00106
         		 −14
    CAP1274
    Figure US20210154213A1-20210527-C00107
         		   55
    CAP1276
    Figure US20210154213A1-20210527-C00108
    CAP1277
    Figure US20210154213A1-20210527-C00109
    CAP1278
    Figure US20210154213A1-20210527-C00110
         		   38
    CAP1279
    Figure US20210154213A1-20210527-C00111
         		   5
    CAP1280
    Figure US20210154213A1-20210527-C00112
         		   44
    CAP1281
    Figure US20210154213A1-20210527-C00113
         		   64
    CAP1347
    Figure US20210154213A1-20210527-C00114
         		   13
    CAP1356
    Figure US20210154213A1-20210527-C00115
         		 −46
    CAP1380
    Figure US20210154213A1-20210527-C00116
         		   16
    CAP1447
    Figure US20210154213A1-20210527-C00117
         		   22
    CAP1450
    Figure US20210154213A1-20210527-C00118
    CAP1451
    Figure US20210154213A1-20210527-C00119
         		   35
    CAP1457
    Figure US20210154213A1-20210527-C00120
    CAP1458
    Figure US20210154213A1-20210527-C00121
         		 −17
    CAP1459
    Figure US20210154213A1-20210527-C00122
         		 −95
    CAP1460
    Figure US20210154213A1-20210527-C00123
         		   1
    CAP1517
    Figure US20210154213A1-20210527-C00124
         		   40
    CAP1518
    Figure US20210154213A1-20210527-C00125
         		 −4
    CAP1519
    Figure US20210154213A1-20210527-C00126
         		   9
    CAP3032
    Figure US20210154213A1-20210527-C00127
         		 −16
    CAP3035
    Figure US20210154213A1-20210527-C00128
         		  114
    CAP3037
    Figure US20210154213A1-20210527-C00129
         		 −2
    CAP3040
    Figure US20210154213A1-20210527-C00130
         		   4
    CAP3042
    Figure US20210154213A1-20210527-C00131
         		 −17
    CAP3062
    Figure US20210154213A1-20210527-C00132
         		   16
    CAP3064
    Figure US20210154213A1-20210527-C00133
         		   12
    CAP3065
    Figure US20210154213A1-20210527-C00134
         		 −32
    CAP3066
    Figure US20210154213A1-20210527-C00135
         		   21
    CAP3067
    Figure US20210154213A1-20210527-C00136
         		−235
    CAP3071
    Figure US20210154213A1-20210527-C00137
         		   30
    CAP3089
    Figure US20210154213A1-20210527-C00138
         		   56
    CAP3107
    Figure US20210154213A1-20210527-C00139
         		   7
    Figure US20210154213A1-20210527-C00140
  • Table 4 below provides EC50 values of select catechol derivatives in preventing Ca+2 and UVC induced aggregation of alpha-A crystalline.
  • TABLE 4
    Compound ID Molecular Structure EC50 (μM)
    CP1194
    Figure US20210154213A1-20210527-C00141
         		1096  
    CAP1042
    Figure US20210154213A1-20210527-C00142
         		 860.3
    CAP1053
    Figure US20210154213A1-20210527-C00143
         		 461.1
    CAP1159
    Figure US20210154213A1-20210527-C00144
         		 312.9
    CAP1160
    Figure US20210154213A1-20210527-C00145
         		 63.5
    CAP1224
    Figure US20210154213A1-20210527-C00146
         		 879.9
    CAP1226
    Figure US20210154213A1-20210527-C00147
         		 46.2
    CAP1227
    Figure US20210154213A1-20210527-C00148
         		 288.1
    CAP1280
    Figure US20210154213A1-20210527-C00149
         		 193.3
    CAP1347
    Figure US20210154213A1-20210527-C00150
         		 115.1
    CAP3089
    Figure US20210154213A1-20210527-C00151
         		 361.9
    • Example 7. Effectiveness of Select Tolcapone Derivatives in Preventing UV- and Heat-Induced Aggregation of Alpha-A Crystalline
  • Table 5 below lists select tolcapone derivatives and their effectiveness in preventing UV-and heat induced aggregation of alpha-A crystalline.
  • TABLE 5
    Cell-based
    Biochemical Cell-based [Heat]
    (UVC) Biochemical [UV] (max (max %
    CAP Assay Assay Ex % net net
    ID Structure (Absorbance) (GEL) Vivo protection) protection)
    1160
    Figure US20210154213A1-20210527-C00152
         		+ + +  68 23
    3089
    Figure US20210154213A1-20210527-C00153
         		 31  0
    1347
    Figure US20210154213A1-20210527-C00154
         		 28  8
    4126
    Figure US20210154213A1-20210527-C00155
         		± ± ND  0
    4127
    Figure US20210154213A1-20210527-C00156
         		+ − ND  55  9
    4128
    Figure US20210154213A1-20210527-C00157
         		+ ± −  23
    4129
    Figure US20210154213A1-20210527-C00158
         		+ + ±  37  0
    4130
    Figure US20210154213A1-20210527-C00159
         		+ − ND  55 42
    4131
    Figure US20210154213A1-20210527-C00160
         		± − ND  0 ND
    4132
    Figure US20210154213A1-20210527-C00161
         		+ − ND  39  0
    4133
    Figure US20210154213A1-20210527-C00162
         		+ + ±  22 18
    4135
    Figure US20210154213A1-20210527-C00163
         		+ ± ±  75  4
    4136
    Figure US20210154213A1-20210527-C00164
         		+ + ±  70  5
    4140
    Figure US20210154213A1-20210527-C00165
         		ND ND
    4151
    Figure US20210154213A1-20210527-C00166
         		ND ND
    4152
    Figure US20210154213A1-20210527-C00167
         		 17  0
    4153
    Figure US20210154213A1-20210527-C00168
         		ND ND
    4160
    Figure US20210154213A1-20210527-C00169
         		+ − ND  82  0
    4161
    Figure US20210154213A1-20210527-C00170
         		± − ND  38  8
    4162
    Figure US20210154213A1-20210527-C00171
         		 60  3
    4172
    Figure US20210154213A1-20210527-C00172
         		+ − ND  67  9
    4173
    Figure US20210154213A1-20210527-C00173
         		+ − ND  61  0
    4196
    Figure US20210154213A1-20210527-C00174
         		 63 38
    4255
    Figure US20210154213A1-20210527-C00175
         		ND ND
    4256
    Figure US20210154213A1-20210527-C00176
         		ND + −  7 ND
    4257
    Figure US20210154213A1-20210527-C00177
         		ND + −  19 ND
    4258
    Figure US20210154213A1-20210527-C00178
         		ND + −  36 ND
    4265
    Figure US20210154213A1-20210527-C00179
         		ND ± ND 129 17
    4269
    Figure US20210154213A1-20210527-C00180
         		ND ND − ND ND
    4270
    Figure US20210154213A1-20210527-C00181
         		ND − ND ND ND
    4271
    Figure US20210154213A1-20210527-C00182
         		ND − ND ND ND
    4272
    Figure US20210154213A1-20210527-C00183
         		ND − ND ND ND
    4279
    Figure US20210154213A1-20210527-C00184
         		ND + ±  5  0
    4281
    Figure US20210154213A1-20210527-C00185
         		ND + −  38  8
    4318
    Figure US20210154213A1-20210527-C00186
         		ND ND
    4324
    Figure US20210154213A1-20210527-C00187
         		ND ND
    • Example 8. Prodrugs of Tolcapone
  • As described above, topical administration is the preferred route for ophthalmic drugs due to its localized drug action at anterior segment of the eye. However, poor penetration and rapid loss of therapeutics following its topical administration are the major restrictions of the topical route. The problem is further amplified and compounded if the given drug has poor aqueous solubility. Formulation approach has been extensively used to address and overcome the poor ocular bioavailability. Besides formulation, chemical approach such as prodrug has been utilized to optimize physicochemical and biochemical properties of a drug molecule for increasing its ocular bioavailability. An essential step in effective prodrug therapy is the activation of the prodrug and the release of the free active therapeutic agent. Important enzymes involved in the activation and bioconversion of prodrugs include phosphatase, paraoxonase, carboxylesterase, acetylcholinesterase, and cholinesterase.
  • Use of tolcapone is associated with side effects, particularly liver injury. Improving solubility of tolcapone, for example, by administering it as a prodrug can lead to the drug being effective at lower doses. To improve the aqueous solubility of tolcapone, a prodrug of tolcapone, CAP4196 was synthesized. It is believed that increased solubility of the prodrug would lead to a more effective treatment of and ocular diseases (presbyopia or cataract), Parkinson's disease, Amyloid diseases, and prevention and/or treatment of transthyretin (TTR)-associated amyloidosis.
    • Synthesis of CAP4196
  • Figure US20210154213A1-20210527-C00188
    • Sodium 2-hydroxy-5-(4-methylbenzoyl)-3-nitrophenyl phosphate, (CAP4196)
  • To a cold solution of Tolcapone (20 g) in THE (100 mL) and Pyridine (25 mL), POCl3 (20 mL) was added drop wise via addition funnel over a period of 20 min. The reaction mixture was stirred at room temperature for overnight and cooled to below 10° C. The reaction was quenched by 50% aq phosphoric acid solution and stirring was continued at RT for 10 hrs. The reaction mixture was further diluted with THE (100 mL) and water (100 mL), precipitated solid was filtered, washed with ethyl acetate (2×50 mL) and dried to afford intermediate 2, Tolcapone monophosphate (8.0 g), as an off-white solid.
  • To a stirred suspension of Tolcapone monophosphate (2) (15 g) in EtOH (300 ml) NaOEt in EtOH (2.5 eq) was added and the suspension stirred for 1 hr. The orange red solid obtained was filtered, washed with EtOH (2×100 ml) and dried to afford 14 g of Tolcapone monophosphate disodium salt, CAP4196 as orange red solid.
  • Solubility: The solubility of CAP1160 and CAP4196 was tested with different FDA approved excipients such as cyclodextrin, PEG-b-PCL, Kolliphor-EL, Kolliphor-40, sorbitol, propelyne gycol, sodium phosphate, etc. Only a 10-fold improvement (1.5 mg/ml) in the solubility of CAP1160 was observed with (2-hydroxypropyl)-beta-cyclodextrin. On the other hand, CAP4196, the phosphate prodrug demonstrated greater than 660-fold improvement (100 mg/ml) in solubility with only water as solvent and the pH of the formulation was 6.65, which is within the pH range of the tears (6.5-7.6). This makes the formulation safe for topical use (see Table 6).
  • TABLE 6
    Solubility of CAP1160 and CAP4196
    FDA approved excipients
    Figure US20210154213A1-20210527-C00189
    Figure US20210154213A1-20210527-C00190
    Solubility in water mg/ml 0.1 100
    Solubility in water with (2-hydroxypropyl)-beta 2   100
    cyclodextrin mg/ml (1:1)
    With PEG-b-PCL (1:1) mg/ml in water 1   ND
    With Kolliphor 40 (1:1) In water 1   ND
    • Example 9: Ocular Safety in New Zealand White Rabbits (NZWR) with Repeated Dose of Prodrug CAP4196 for 7 Days
  • Prodrug CAP4196 is well-tolerated up to 10% concentration in New Zealand white rabbits. Initial maximum tolerated dose studies (MTD) help identify observable signs of toxicity and provide a rationale for setting dose levels in later definitive studies. Therefore, the MTD of CAP4196 was evaluated in New Zealand white rabbits. Four animals per group were dosed with increasing concentrations (0.25, 2.5, 8 and 10%) of CAP4196 at 50 μl volume q.i.d. dosing at 2 hrs interval. Following the dosing, the animals were evaluated for mortality and morbidity, ophthalmological examination, body weight, and clinical pathology before start of dosing then on dosing days 2, 4, and 6 prior to first dose instillation and on day 7, one hour after last dose instillation.
  • Based on the results, it was concluded that administration of CAP4196 (50 μL 4 times a day with an interval of 2 hours in between each dosing) at dose concentration of 10% w/v produced only few temporary local reactions like excessive rubbing of eyes and redness and did not produced any systemic toxicity in New Zealand white rabbits followed in this MTD study. Hence, the highest dose concentration of 10% was considered as the MTD. See Table 7.
  • TABLE 7
    Toxicity results of CAP4196
    Total No Mortality
    Group of and
    No Group Details Dose Level Sex Animals Morbidity
    G1 CAP4196 ophthalmic 50 μL × 4 times a day Male 3 0
    formulation (0.25% w/v) in each eye
    G2 CAP4196 ophthalmic 50 μL × 4 times a day Male 3 0
    formulation (4% w/v) in each eye
    G3 CAP4196 ophthalmic 50 μL × 4 times a day Male 3 0
    formulation (8% w/v) in each eye
    G4 CAP4196 ophthalmic 50 μL × 4 times a day Male 3 0
    formulation (10% w/v) in each eye
    • Example 9. Tolcapone Derivatives in Prevention or Treatment of Transthyretin and Parkinson's Disease
  • Transthyretin (TTR) is a plasma homotetrameric protein with a role in fatal systemic Amyloidosis (Sant'Anna, R. et al. (2016) Nat. Commun. 7:10787 doi: 10.1038/ncomms10787). TTR tetramer dissociation precedes pathological TTR aggregation. Native state
  • stabilizers of the TTR tetramer are promising drugs to treat TTR amyloidoses. Tolcapone, an FDA-approved molecule for Parkinson's disease, is a potent TTR aggregation inhibitor (Sant'Anna, R. et al. (2016)). Tolcapone binds specifically to TTR in human plasma, stabilizes the native tetramer in vivo in mice and humans and inhibits TTR cytotoxicity ((Sant'Anna, R. et al. (2016). As such, tolcapone believed to be a strong candidate for treating TTR amyloidosis. Since tolcapone use is associated with side effects, particularly liver injury, and improving solubility of tolcapone, for example, by administering it as a prodrug can lead to the drug being effective at lower dose, it is contemplated that prodrugs of tolcapone described herein would be better as therapeutics against TTR amyloidosis and Parkinson's disease.
    • Example 10: Structure Activity Relationship of Naphthalene Analogs
  • Structure activity relationship of Naphthalene analogs are summarized in Table 8 below.
  • TABLE 8
    Cell UV Cell Heat
    % %
    ID Structure Biochemical Gel Ex-vivo protection protection
    CAP4179
    Figure US20210154213A1-20210527-C00191
         		+ + ND 61 29
    CAP4180
    Figure US20210154213A1-20210527-C00192
         		+ + + 53 22
    CAP4183
    Figure US20210154213A1-20210527-C00193
         		+ + + 82 17
    CAP4184
    Figure US20210154213A1-20210527-C00194
         		+ + 15% 49  4
    CAP4186
    Figure US20210154213A1-20210527-C00195
         		+ + ND 54 17
    CAP4187
    Figure US20210154213A1-20210527-C00196
         		+ + + 62 19
    CAP4188
    Figure US20210154213A1-20210527-C00197
         		+ + ND  0  2
    CAP4190
    Figure US20210154213A1-20210527-C00198
         		65 15
    CAP4209
    Figure US20210154213A1-20210527-C00199
         		 0
    CAP4210
    Figure US20210154213A1-20210527-C00200
         		 1
    CAP4211
    Figure US20210154213A1-20210527-C00201
         		 0
    CAP4212
    Figure US20210154213A1-20210527-C00202
         		 0
    CAP4213
    Figure US20210154213A1-20210527-C00203
         		14
    CAP4214
    Figure US20210154213A1-20210527-C00204
         		− 86
    CAP4215
    Figure US20210154213A1-20210527-C00205
         		− 46
    CAP4216
    Figure US20210154213A1-20210527-C00206
         		− 49
    CAP4217
    Figure US20210154213A1-20210527-C00207
         		− 41
    CAP4218
    Figure US20210154213A1-20210527-C00208
         		− 38
    CAP4221
    Figure US20210154213A1-20210527-C00209
         		50
    CAP4222
    Figure US20210154213A1-20210527-C00210
         		− 27
    CP01191
    Figure US20210154213A1-20210527-C00211
         		− 23
    CAP4223
    Figure US20210154213A1-20210527-C00212
         		16
    CAP4224
    Figure US20210154213A1-20210527-C00213
         		 0
    CP01181
    Figure US20210154213A1-20210527-C00214
         		11
    CP0098
    Figure US20210154213A1-20210527-C00215
         		 1
    CAP4225
    Figure US20210154213A1-20210527-C00216
         		+ +  3
    CP01185
    Figure US20210154213A1-20210527-C00217
         		13
    CAP4226
    Figure US20210154213A1-20210527-C00218
         		18
    CP0080
    Figure US20210154213A1-20210527-C00219
         		+ − 47
    CP0103
    Figure US20210154213A1-20210527-C00220
         		66
    CAP4227
    Figure US20210154213A1-20210527-C00221
         		38
    CP01189
    Figure US20210154213A1-20210527-C00222
         		13
    CAP4228
    Figure US20210154213A1-20210527-C00223
         		 4
    CAP4230
    Figure US20210154213A1-20210527-C00224
         		+ − 51
    CP0094
    Figure US20210154213A1-20210527-C00225
         		55
    CP0098
    Figure US20210154213A1-20210527-C00226
         		+  1
    CP0110
    Figure US20210154213A1-20210527-C00227
         		−  3
    CP1101
    Figure US20210154213A1-20210527-C00228
         		−  0
    • EQUIVALENTS
  • All the features disclosed in this specification may be combined in any combination. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, each feature disclosed is only an example of a generic series of equivalent or similar features.
  • From the above description, one skilled in the art can easily ascertain the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Thus, other embodiments are also within the scope of the following claims.

Claims (21)

1. A method for treating presbyopia or cataract in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having the formula (VII)
Figure US20210154213A1-20210527-C00229
or a solvate or a pharmaceutically acceptable salt thereof, wherein
R1 is independently selected from the group consisting of hydrogen; (C1-C3)alkyl; halo(C1-C3)alkyl; (C3-C6)cycloalkyl; halo(C3-C10)cycloalkyl; (C1-C3)alkyloxy; and R4C═O; wherein R4 is selected from the (C1-C6)alkyl; halo(C1-C6)alkyl; (C3-C6)cycloalkyl; halo(C3-C6)cycloalkyl; aryl; haloaryl; and
Figure US20210154213A1-20210527-C00230
 wherein R7 is (C1-C6)alkyl and R is (C1-C6)alkyl, aryl, or a polyethylene glycol group;
R2 is independently selected from the group consisting of hydrogen, R5, OR5, N(R5)(R6), halide, CN, NO2, C(O)OR5, CON(R5)(R6), S(O)NR5 2, SO3H, SO2CH3, phenyl, biphenyl, phenoxy-phenyl, and polyethyleneglycol groups, wherein R and R′ are independently selected from hydrogen atom, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C3-C6)cycloalkyl(C1-C6)alkyl, halo(C3-C6)cycloalkyl(C1-C6)alkyl, and (C3-C6)cycloalkylhalo(C1-C6)alkyl groups; wherein R2 can occupy 0-2 positions in the ring of its occurrence; and wherein, in the event any two adjacent groups selected are OR5 groups, the two OR5 groups may optionally be cross-linked via their R5 functionalities to form an additional ring; and
R3 is selected from the group consisting of hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, halo(C3-C6)cycloalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl, and hydroxy(C2-C6)alkenyl.
2. The method of claim 1, wherein the compound is
Figure US20210154213A1-20210527-C00231
wherein
R1 is independently selected from the group consisting of
Figure US20210154213A1-20210527-C00232
wherein R7 is (C1-C6)alkyl and R8 is (C1-C6)alkyl, aryl, or a polyethylene glycol group.
3. The method of claim 1, wherein each R1 is a hydrogen atom.
4. The method of claim 1, wherein each R1 is an alkyl.
5. The method of claim 1, wherein one R1 is a hydrogen or an alkyl, and the other R1 is R4C═, wherein R4 is CH3 or C6H5.
6. The method of claim 1, wherein the compound is
Figure US20210154213A1-20210527-C00233
Figure US20210154213A1-20210527-C00234
7-114. (canceled)
115. A method of preventing and/or treating transthyretin (TTR)-associated amyloidosis in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having the formula
Figure US20210154213A1-20210527-C00235
or a pharmaceutically acceptable salt thereof,
wherein R1 is independently selected from the group consisting of
Figure US20210154213A1-20210527-C00236
and hydrogen such that only one R1 is hydrogen,
wherein R is (C1-C6)alkyl and R8 is (C1-C6)alkyl, aryl, or a polyethylene glycol group.
116. The method of claim 115, wherein the compound is
Figure US20210154213A1-20210527-C00237
117. A method of treating Parkinson's disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a compound having the formula
Figure US20210154213A1-20210527-C00238
wherein R1 is independently selected from the group consisting of hydrogen,
Figure US20210154213A1-20210527-C00239
wherein R7 is (C1-C6)alkyl and R8 is (C1-C6)alkyl, aryl, or a polyethylene glycol group.
118. The method of claim 117, wherein the compound is
Figure US20210154213A1-20210527-C00240
119. The method of claim 1, wherein one of the two R1 is
Figure US20210154213A1-20210527-C00241
120. The method of claim 1, wherein R2 is hydrogen and one of the two R1 is
Figure US20210154213A1-20210527-C00242
121. The method of claim 1, wherein R2 is hydrogen and one of the two R1 is R4C═O, wherein is R4 is (C1-C6)alkyl or an aryl.
122. The method of claim 1, wherein both R1 and R2 are hydrogen.
123. The method of claim 1, wherein R2 is hydrogen and one of the two R1 is OH
Figure US20210154213A1-20210527-C00243
124. The method of claim 123, wherein R7 is a methyl, ethyl, or a propyl group.
125. The method of claim 1, wherein R2 is hydrogen and both R1 are
Figure US20210154213A1-20210527-C00244
126. The method of claim 125, wherein R7 is a methyl, ethyl, or a propyl group.
127. The method of claim 1, wherein R2 is hydrogen and one of the two R1 is
Figure US20210154213A1-20210527-C00245
wherein R8 is a (C1-C6)alkyl or an aryl.
128. The method of claim 1, wherein R2 is hydrogen and one of the two R1 is
Figure US20210154213A1-20210527-C00246
wherein R8 is a polyethylene glycol.
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